On-water vinylogous mukaiyama-michael addition of heterocyclic 2-silyloxydienes to 1,2-diaza-1,3-dienes: one-pot three-step entry to functionality-rich pyrroles

Article abstract of DOI:10.1002/adsc.201100296

Densely substituted pyrrole-carboxylates have been prepared in good yields in a highly practical one-pot three-step procedure. The key reaction of this process, which involves an uninterrupted sequence of reactions on-water, is a diastereoselective vinylogous Mukaiyama-Michael addition reaction (VMMcR) of heterocyclic 2-silyloxydienes to 1,2-diaza-1,3-dienes mediated by water itself. Subsequent in situ addition of catalytic aqueous sodium carbonate promotes an intramolecular aza-Michael addition with final ring-opening and aromatization. The superior use of water in the VMMcR as both reaction medium and promoter vis-a-vis deployment of conventional Lewis acids in organic solvents is highlighted, which provides the best results in terms of reaction rate, efficiency, stereoselectivity, and overall practicality. Copyright

Full text of DOI:10.1002/adsc.201100296

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DOI: 10.1002/adsc.201100296
On-Water Vinylogous Mukaiyama–Michael Addition of
Heterocyclic 2-Silyloxydienes to 1,2-Diaza-1,3-dienes: One-Pot
Three-Step Entry to Functionality-Rich Pyrroles
Lucia Battistini,a,* Luca Dell’Amico,a Andrea Sartori,a Claudio Curti,a
Giorgio Pelosi,b Giovanni Casiraghi,a Orazio A. Attanasi,c Gianfranco Favi,c
and Franca Zanardia,*
a
Dipartimento Farmaceutico, Universitꢀ degli Studi di Parma, Parco Area delle Scienze 27A, 43124 Parma, Italy
Fax : (+39)-05-21-90-5006; phone: (+39)-05-21-90-6040 (L.B.), (+39)-05-21-90-5067 (F.Z.); e-mail: lucia.battistini@unipr.it
or franca.zanardi@unipr.it
b
Dipartimento di Chimica Generale ed Inorganica, Chimica Analitica, Chimica Fisica, Universitꢀ degli Studi di Parma,
Parco Area delle Scienze 17A, 43124 Parma, Italy
Istituto di Chimica Organica, Universitꢀ degli Studi di Urbino “Carlo Bo”, Via I Maggetti 24, 61029 Urbino, Italy
c
Received: April 19, 2011; Published online: August 10, 2011
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adcs.201100296.
Abstract: Densely substituted pyrrole-carboxylates
have been prepared in good yields in a highly prac-
tical one-pot three-step procedure. The key reaction
of this process, which involves an uninterrupted se-
quence of reactions on-water, is a diastereoselective
vinylogous Mukaiyama–Michael addition reaction
(VMMcR) of heterocyclic 2-silyloxydienes to 1,2-
diaza-1,3-dienes mediated by water itself. Subse-
quent in situ addition of catalytic aqueous sodium
carbonate promotes an intramolecular aza-Michael
addition with final ring-opening and aromatization.
The superior use of water in the VMMcR as both
reaction medium and promoter vis-ꢀ-vis deploy-
ment of conventional Lewis acids in organic sol-
vents is highlighted, which provides the best results
in terms of reaction rate, efficiency, stereoselectiv-
ity, and overall practicality.
The ever increasing awareness of the utility of
water in organic synthesis is rooted on diverse, key
contributions, which include the seminal investiga-
tions by Breslow and co-workers[2] who first reported
quantitative studies on the effect of water as a rate-
and selectivity-enhancing medium in Diels–Alder cy-
cloaddition reactions in dilute homogeneous solutions.
Practical and semantic stigmatization on this subject
matter was then offered by Sharpless and colleagues[3]
who showed how chemical reactions carried out on-
water – that is under strictly aqueous, heterogeneous
conditions on a preparative scale – could benefit from
marked advantages in terms of synthetic efficiency,
stereochemical control, and overall practicality as
well.
Furthermore, an evermore ecological perception of
chemical transformations, which tend to emulate the
ideal reaction conditions of biochemical processes
within the living organisms, has fuelled such a general
interest toward aqueous-based organic reactions.
Lastly, a couple of additional key points contribute
to support the “resurgence” of aqueous media in or-
ganic synthesis, i.e., (i) the introduction of novel
water-tolerant reactants and catalytic systems in the
organic synthesis palette,[4] and (ii) the skillful inter-
Keywords: 1,2-diaza-1,3-dienes; green chemistry;
nitrogen heterocycles; silyloxydienes; vinylogous
Mukaiyama–Michael reaction
The past two decades have witnessed a blossom of re- vention of talented theoreticians who furnished (and
search articles among the organic chemistry assembly still are furnishing) a robust background of thermody-
where the bulk of reactions which were historically namic, kinetic, and computational studies to support
carried out in organic solvents have been revisited in and rationalize results in this often cryptic field.[5]
an aqueous environment, be it as the sole reaction
Among the classical organic reactions which have
medium, be it in the presence of accompanying co- been revisited under an aqueous perspective, the Mu-
solvents or excess solubilizing organic reactants.[1]
kaiyama–Michael addition reaction[6] – that is the
1966
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Adv. Synth. Catal. 2011, 353, 1966 – 1972

On-Water Vinylogous Mukaiyama–Michael Addition of Heterocyclic 2-Silyloxydienes
Scheme 1. Exploiting the d4 reactivity of 2-silyloxyheterocycles I (left) and the a4 reactivity of 1,2-diaza-1,3-dienes II (right).
(LA=Lewis acid; VMAR=vinylogous Mukaiyama aldol reaction; VMMnR=vinylogous Mukaiyama–Mannich reaction;
VMMcR=vinylogous Mukaiyama–Michael reaction).
Lewis acid-promoted conjugate addition of silyl enol cussed, leading to functionality-rich pyrrole-carboxy-
ether (or silyl ketene acetal) donors to a,b-unsaturat- lates in good yields and outstanding practicality.
ed carbonyl acceptors – has received only scant atten-
We began our studies with the model reaction be-
tion,[7,8] possibly because of the inherent lability of tween N-tert-butoxycarbonyl-2-[(tert-butyldimethyl)si-
both silyl enolates and common Lewis acid promoters lyloxy]pyrrole (1a) and ethoxycarbonyl-substituted di-
towards hydrolysis. Accounts on the use of water in azadiene 2a, which was screened with conventional
the vinylogous version of the Mukaiyama–Michael re- Lewis acid promoters in CH2Cl2 (Table 1). Using
action, which deploys vinylogous silyl enolate BF3·OEt2 in both stoichiometric and catalytic quanti-
donors,[9] have not been reported so far.
ties at À788C produced very poor results (not
During ongoing studies in the field of vinylogous shown),[13] while catalytic amounts of the same Lewis
Mukaiyama-type aldol, Mannich, and Michael addi- acid at 258C ensured good levels of conversion to the
tions, we came to appreciate the virtues of diverse expected Michael adduct 3a, which was recovered as
heterocyclic 2-silyloxydienes of type I (Scheme 1, left) a separable 70:30 syn:anti diastereomeric mixture
which may act as useful d4 reactants in coupling addi- (entry 1).
tions to carbonyl compounds, aldimines, or electron-
Similar conversions and reaction rates were ob-
served with other Lewis acid catalysts, albeit with
deficient alkenes.[9]
Typically, these reactions were performed in the syn:anti stereoselectivities varying from fairly good to
presence of stoichiometric amounts of Lewis acid pro- poor. Significantly, the presence of the Lewis acid
moters in CH2Cl2 or Et2O as solvent.[10] On the other component turned out to be essential, since the reac-
hand, long-standing experience matured in the use of tion between the sole 1a and 2a in CH2Cl2 gave no
1,2-diaza-1,3-dienes[11] of type II as precious a4 syn- detectable amounts of product (entry 3). Variation of
thons in a multitude of Michael-type addition reac- the donor reactant was also scrutinized. Change of
tions including Mukaiyama–Michael-type process[11a,b] the TBS for a TMS group in the pyrrole 1 resulted in
(Scheme 1, right), has prompted us to investigate the a significant rate acceleration of the reaction (3 h vs.
behaviour of these substrates with diverse heterocy- 6 h, entry 4 vs. 2), while both efficiency and stereose-
clic 2-silyloxydienes. In general, the Mukaiyama ver- lectivity remained almost untouched.
sion of the Michael reaction of silyl enol ethers was
By deployment of commercial 2-(trimethylsilyloxy)-
performed under the agency of catalytic amounts of furan (1c), the coupling reaction to 2a in the presence
Lewis acid activators in organic solvents to furnish of various Lewis acid catalysts occurred with equally
1,4-hydrazonic adduct intermediates eventually lead- complete g-regioselection, affording the correspond-
ing to the nitrogen-containing heterocyclic target ing butenolide product 3b in satisfactory yields albeit
compounds.[11a,b,12]
with very modest diastereoselection (e.g., entry 5). As
Herein, the ability of heterocyclic 2-silyloxydienes an exception, the Sc(OTf)3-catalyzed reaction involv-
AHCTUNGTRENNUNG
to couple to 1,2-diaza-1,3-dienes according to a vinyl- ing thiophene-derived silyl ether 1d was unsuccessful,
ogous Mukaiyama–Michael reaction (VMMcR) mo- possibly because of the rapid degradation of the labile
dality under both a traditional organic environment thiobutenolide vinylogous Michael product under
and in an aqueous medium is assayed and compared. these reaction conditions (entry 6).
Exploitation of the emerging vinylogous Michael ad-
The relative configuration of the major pyrrolinone
ducts in all-on-water one-pot procedures is also dis- product syn-3a was unambiguously certified by single
Adv. Synth. Catal. 2011, 353, 1966 – 1972
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1967

Lucia Battistini et al.
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Table 1. Screening conditions for organic-phase VMMcR using heterocyclic silyloxydienes 1 and 1,2-diaza-1,3-diene 2a.
Entry
Donor
R3Si
X
Lewis acid (mol%)
BF3·OEt2 (10)
Product[b]
Conversion [%][c]
g:a[c]
dr (syn:anti)[c,d]
1
2
1a
1a
1a
1b
1c
1d
1b
TBS
TBS
TBS
TMS
TMS
TMS
TMS
NBoc
NBoc
NBoc
NBoc
O
3a
3a
–
80
92
–
96
72
–
>99:1
>99:1
–
>99:1
>99:1
–
70:30
78:22
–
78:22
67:33
–
Sc
–
ACHTUNGRTENN(UNG OTf)3 (10)
3
4[e]
5
Sc
Sc
Sc
Sc
N
3a
3b
[f]
6
S
–
7[g]
NBoc
3a
85
>99:1
77:23
[a]
Unless otherwise noted, reactions were performed with silyloxydiene 1/1,2-diaza-1,3-diene 2a (1.15/1.00 mol equiv.),
Lewis acid (mol%), with a substrate concentration of 0.06M (0.19 mmol scale) in dry CH2Cl2, at 258C under an argon at-
mosphere, with a 6 h reaction time. For details, see Supporting Information.
[b]
[c]
[d]
[e]
[f]
Racemic syn/anti product.
1
Determined by H NMR analysis of the crude reaction product.
Relative configuration of 3a certified by X-ray analysis of syn-4a (see text for details).
Reaction time 3 h.
Degradation products detected.
[g]
Substrate concentration of 0.14M (0.7 mmol scale); reaction time 48 h.
crystal X-ray analysis of its saturated counterpart, role 1b and 1,2-diaza-1,3-diene 2a, on a 0.7 mmol
namely compound syn-4a, as illustrated in Figure 1. preparative scale in 0.14M solutions. We soon realiz-
At this point, in recognizing the feasibility of the ed that the presence of water either as the sole reac-
VMMcR between heterocyclic silyloxydienes and 1,2- tion medium or in the co-presence of other polar sol-
diaza-1,3-dienes under conventional organic routes, vents or salts could expedite the reaction rates up to
we next wondered whether this valuable carbon- 20 times as compared to the full organic counterparts
carbon bond-forming reaction could be further digni- (cf. entry 7 in Table 1), producing the expected
fied by the use of viable aqueous procedures.
VMMcR products in high yields and selectivities
At first we screened conditions for the model reac- (Table 2). Significant rate increases (by 9 to 24 times,
tion between the highly reactive TMS-protected pyr- entries 3 and 5 vs. 11) were observed over reactions
Figure 1. ORTEP representation of the X-ray structure of racemic derivative syn-4a; the (2S,2’R)-enantiomer is shown.
1968
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On-Water Vinylogous Mukaiyama–Michael Addition of Heterocyclic 2-Silyloxydienes
Table 2. Screening conditions for aqueous, open-air VMMcR using heterocyclic silyloxydienes 1 and 1,2-diaza-1,3-diene 2a.[a]
Entry
Donor
R3Si
X
Solvent
Temp.
[8C]
Time
[h]
Prod-
uct[b]
Yield
[%][c]
g:a[d]
dr
ACHTUNGTRENNUNG
(syn:anti)[d,e]
1[f,g]
2[f]
3
4
5
1b
1b
1b
1b
1b
1a
1b
1b
1c
1d
1b
TMS
TMS
TMS
TMS
TMS
TBS
TMS
TMS
TMS
TMS
TMS
NBoc
NBoc
NBoc
NBoc
NBoc
NBoc
NBoc
NBoc
O
H2O/MeOH (1:1)
H2O/MeOH (1:1)
H2O/MeOH (1:1)
H2O/t-BuOH (1:1)
H2O
H2O
H2O
brine
H2O
H2O
neat
25
24
8
8
48
3
3.5
24
2.5
2
3a
3a
3a
3a
3a
3a
3a
3a
3b
3c
3a
45
95
90
75
96
82
97.5
90
53
87
55
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
89:11
80:20
80:20
56:45
80:20
>99:1
80:20
>99:1
>99:1
63:37
77:23
38–40
38–40
38–40
38–40
38–40
25
38–40
38–40
38–40
38–40
6
7[g]
8
9
10
11
S
1.5
72
NBoc
[a]
Unless otherwise noted, reactions were performed with silyloxydiene 1/1,2-diaza-1,3-diene 2a (1.15/1.00 mol equiv.), with
a substrate concentration of 0.14M (0.7 mmol scale) in the indicated solvent, in air, at atmospheric pressure under sonica-
tion (59 KHz). For details, see Experimental Section.
[b]
[c]
[d]
[e]
[f]
Racemic syn/anti product.
Combined isolated yield.
1
Determined by H NMR analysis of the crude reaction product.
Relative configuration of 3a certified by X-ray analysis of syn-4a (see text for details).
Carried out in the presence of ScACHTNUGTRENNUNG
[g]
carried out in the absence of any solvent, indicating
that rate acceleration could not be ascribed to the tion may be performed utilizing either TBS-protected
sole increasing concentration effect. pyrrole 1a in pure water (entry 6) or pyrrole 1b in
The presence of catalytic, water-tolerant Lewis brine (entry 8). However, both reactions suffer from
acids [for example, Sc
(OTf)3] turned out to be super- slightly diminished yields and scant practicality.[15]
fluous, since its depletion did not compromise the ef- Noticeably, this on-water procedure could be conven-
To access diastereomerically pure syn-3a, the reac-
AHCTUNGTRENNUNG
fectiveness of the transformation (entries 1 and 2 vs. iently extended to oxygen- and sulphur-containing nu-
3-8). Conducting the reaction under ultrasonic irradia- cleophiles (entries 9 and 10); both reactions proceeded
tion, on the other hand, did produce significantly en- speedly (2 h and 1.5 h), with clean recovery of the corre-
hanced reaction rates by 3 to 8 times (entries 1 vs. 2 sponding butenolide-type products 3b and 3c in accepta-
and 5 vs. 7).
ble-to-good yields and diastereomeric ratios.[16]
Using an H2O/MeOH (1:1) solvent mixture, reac-
To demonstrate the synthetic potential of the dis-
tants 1b and 2a completely dissolved in the reaction closed on-water procedure, a one-pot methodology
medium and afforded the vinylogous Michael product was assayed which involved addition of catalytic
3a in high yields, with exclusive g-site selectivity and aqueous carbonate solution to the open-air reaction
80:20 syn:anti dr (entry 3). On the other hand, by vessel at ambient temperature once the conversion of
adding liquid pyrrole 1b and solid 1,2-diaza-1,3-diene the starting reactants 1b and 2a to 3a was judged com-
2a sequentially in an open-air water medium under plete (Scheme 2). After 17 h, water-insoluble pyrrole
59 KHz sonication at 38–408C (entry 5), a heteroge- 5a formed, which could be isolated as a pure solid in
neous suspension of finely dispersed reactants 51% overall yield by simple filtration.
formed, with concomitant color turning from dark-red
Mechanistically, we surmised[17] that, after the initial
to pale-yellow. After 3 h, precipitation of a yellowish formation of the Michael adduct 3a, the added base
solid decretes the reaction conclusion.[14] Compound triggers a cascade of events featuring an intramolecu-
3a is recovered in >99% conversion by simple filtra- lar aza-Michael reaction to furnish a diazabicyclo-
tion and extraction as an 80:20 syn:anti diastereo-
ACHTUNGTREN[NGNU 3.3.0] intermediate, which is promptly subjected to
meric mixture.
ring opening and aromatization to pyrrole 5a.
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Lucia Battistini et al.
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action took place either when the carbamoyl group at
N-1 was replaced by a phenylamino function, or the
ester moiety at C-4 was substituted by an amide
group; and this is possibly due to a LUMO rise of the
azadiene C-4 carbon atom.
As for the dramatic role exerted by water in this
transformation, we assume that concurrent on-water
and in-water phenomena may occur and multiple fac-
tors may simultaneously operate, which involve hy-
drophobic effects, trans-phase H-bonding, and solvent
polarity effects. Specifically, for those reactions car-
ried out under heterogeneous conditions, one or more
water molecules at the boundary between the sub-
strate particles and water are speculated to activate
the reactants and strictly control their mutual position
in the transition states.[1e–h,5c–e]
In conclusion, we have described highly practical
and efficient methods that allow for the direct con-
struction of varied heteroatom-carrying hydrocarbon
skeletons. In particular, the first vinylogous Mukaiya-
ma–Michael addition reaction has been reported,
where heterocyclic 2-silyloxydienes and 1,2-diaza-1,3-
dienes are coupled on-water in open-air vessels under
ultrasound irradiation at 38–408C. The butenolide-
type Michael products obtained (compounds 3) are
either easily isolated, or may they be involved in a
base-triggered, all-in-water reaction cascade ultimate-
ly resulting in production of differently adorned pyr-
role-carboxylates. This one-pot, three-step procedure
can come very close to ideal green conditions[19] since
it condenses optimal requisites such as efficiency,
atom economy, safety, reaction speed, preparative
usefulness, and easy of product isolation.
Scheme 2. Profiling the scope of the VMMcR on water (iso-
lated yields for the one-pot three-step procedure from the
corresponding 1,2-diaza-1,3-diene, in parenthesis).
Instructive is also the direct comparison between
the on-water VMMcR procedure and the “organic”
counterpart carried out using conventional Lewis acid
promoters and organic solvents; the superior role of
water in terms of reaction rate, stereoselectivity, effi-
Pyrroles of type 5a are functionally dense heterocy- ciency and general applicability has been widely dem-
cles from which several diverse products may, in prin- onstrated.
ciple, be generated. For instance, oxidative or reduc-
Finally, while the interpretation of the actual role
[18]
À
tive N N cleavage
may furnish nitrogen-free pyr- exerted by water during these processes remains
role-carboxylates, while saturation of the pyrrole largely speculative, this study may furnish a further
carbon-carbon double bonds may lead to unusual yet piece in unravelling the fundamental actions that
intriguing homoproline b-amino acid privileged struc- govern the on-water catalysis at the molecular level.
tures.
On the basis of these results, we were able to
extend the one-pot three-step protocol to variously
Experimental Section
substituted azo-ene substrates. As shown in Scheme 2,
a panel of variously adorned pyrrole-carboxylates
5b–e was easily accessed in overall yields ranging
from 41 to 57% from the respective 1,2-diaza-1,3-
dienes 2b–e, with no need for any chromatographic
intervention.
On-Water One-Pot Three-Step Synthesis of Pyrroles
5a-e. Preparation of Ethyl 5-[(tert-butoxycarbonyl-
carbamoyl)methyl]-2-methyl-1-ureido-1H-pyrrole-3-
carboxylate (5a)
This transformation proved sensitive to the nature
of the substituents at the N-1 and C-4 positions of the
To
a suspension of 1,2-diaza-1,3-diene (2a) (130 mg,
0.7 mmol) in water (5 mL) under sonication at 38–408C in
starting 1,2-diaza-1,3-diene reactant. As a rule, no re- an open-air vessel, pyrrole 1b (206 mg, 0.81 mmol) was
1970
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On-Water Vinylogous Mukaiyama–Michael Addition of Heterocyclic 2-Silyloxydienes
added. After 1 h the solution turned from red to orange,
and to a pale yellow color after 3 h reaction. At this point
the reaction was monitored by TLC (EtOAc/MeOH 98:2)
to check the complete disappearance of 1,2-diaza-1,3-diene
2a. Sodium carbonate (7.4 mg, 0.07 mmol) was then added,
the reaction vessel was removed from the ultrasound bath
and the solution was kept under magnetic stirring for 17 h at
room temperature. Filtration of the reaction mixture gave
the pure pyrrole-carboxylate 5a as a white solid without
need of further purification; yield: 131.5 mg (51% yield for
three steps from 2a); mp 1418C. IR (KBr): n=3454, 3342,
[3] S. Narayan, J. Muldoon, M. G. Finn, V. V. Fokin, H. C.
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;
(300 MHz, CDCl3): d=8.40 (bs, 1H, NH), 8.06 (s, 1H, NH),
6.43 (s, 1H, H-4), 4.88 (bs, 2H, NH2), 4.25 (q, J=7.1 Hz,
2H, CH3CH2O), 4.17 (d, J=18.0 Hz, 1H, H-1’a), 3.85 (d, J=
18.0 Hz, 1H, H-1’b), 2.46 (s, 3H, CH3), 1.50 (s, 9H, t-Bu),
1.31 (t, J=7.1 Hz, 3H, CH3CH2O); 13C NMR (75 MHz,
CDCl3): d=174.2 (Cq, C-2’), 165.0 (Cq, CO2Et), 158.4 (Cq,
CONH2), 151.0 (Cq, Boc), 137.7 (Cq, C-2), 124.9 (Cq, C-5),
111.2 (Cq, C-3), 109.1 (CH, C-4), 83.5 (Cq, t-Bu), 59.9 (CH2,
CH3CH2O), 33.9 (CH2, C-1’), 28.2 (3C, CH3, t-Bu), 14.7
(CH3, CH3CH2O), 10.8 (CH3, Me); Rf 0.18 (8:2 acetone/
hexane); MS (ESI+): m/z=291.3 [MÀBoc+Na]+; 391.2
[M+Na]+; anal. calcd. for C16H24N4O6 (368.38): C 52.17, H
6.57, N 15.21; found: C 52.23, H 6.60, N 15.15.
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[7] A single example of water-promoted Mukaiyama–Mi-
chael reaction between 1-trimethylsilyloxycyclohexene
and methyl vinyl ketone was described. Using a H2O/
THF solvent mixture under ultrasonic irradiation for
24 h at 558C, the expected Michael product was ob-
tained in a 32% isolated yield. The procedure was not
effective using acrolein: A. Lubineau, E. Meyer, Tetra-
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Supporting Information
Description of experimental procedures, characterization
data, crystal data for compound syn-4a, and selected NMR
spectra are available as Supporting Information.
Acknowledgements
Funding from Universitꢀ degli Studi di Parma and Universitꢀ
degli Studi di Urbino is gratefully acknowledged. The authors
thank the Centro Interdipartimentale Misure “G. Casnati”
(Universitꢀ degli Sudi di Parma) for instrumental facilities
and Dr. Luca Amadei for preliminary organic-phase experi-
ments.
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Adv. Synth. Catal. 2011, 353, 1966 – 1972