Aqueous and solvent-free uncatalyzed three-component vinylogous mukaiyama-mannich reactions of pyrrole-based silyl dienolates

Article abstract of DOI:10.1002/adsc.201100572

A catalyst-free, environmentally benign three-component vinylogous Mukaiyama-Mannich reaction of pyrrole-based silyl dienolates is presented, which works effectively in both aqueous and solvent-free environments. Both lipophilic and hydrophilic aldehyde c

Full text of DOI:10.1002/adsc.201100572

COMMUNICATIONS
DOI: 10.1002/adsc.201100572
Aqueous and Solvent-Free Uncatalyzed Three-Component
Vinylogous Mukaiyama–Mannich Reactions of Pyrrole-Based
Silyl Dienolates
Andrea Sartori,a,* Luca Dell’Amico,a Claudio Curti,a Lucia Battistini,a
Giorgio Pelosi,b Gloria Rassu,c Giovanni Casiraghi,a and Franca Zanardia,*
a
Dipartimento Farmaceutico, Universitꢀ degli Studi di Parma, Parco Area delle Scienze 27A, 43124 Parma, Italy
Fax : (+39)-0521-905006; phone: (+39)-0521-905079 (A.S.), (+39)-0521-905067 (F.Z.); e-mail: andrea.sartori@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 17 A, 43124 Parma, Italy
Istituto di Chimica Biomolecolare del CNR, Traversa La Crucca 3, I-07100 Li Punti, Sassari, Italy
c
Received: July 19, 2011; Revised: September 10, 2011; Published online: December 8, 2011
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adcs.201100572.
Abstract: A catalyst-free, environmentally benign
three-component vinylogous Mukaiyama–Mannich
reaction of pyrrole-based silyl dienolates is present-
ed, which works effectively in both aqueous and
solvent-free environments. Both lipophilic and hy-
drophilic aldehyde candidates are suitable sub-
strates, allowing access to a rich repertoire of unsa-
turated vicinal aminolactam structures with virtually
complete g-site selectivity and moderate to good
anti-diastereoselectivity. The utility of this technolo-
gy is highlighted by protecting group-free synthesis
of densely hydroxylated, sugar-related lactam
frameworks. The role of water as an indispensable
H-bonding reaction propeller is demonstrated.
As for the Mannich reaction in particular, signifi-
cant progress has been made for direct and indirect,
two-component and three-component executions, few
of which adopting neutral water as the reaction
medium or even under solvent-free conditions.[5]
However, to the best of our knowledge, there are not
examples available concerning the development of
catalyst-free, aqueous or neat Mukaiyama-type vinyl-
ogous Mannich addition methodology,[8,9] in spite of
the distinct advantage of being atom conservative and
more eco-friendly as compared to the conventional
organic-phase, catalyzed counterparts. To address this
issue, in connection with our ongoing studies focused
on the exploitation of heterocyclic silyl dienolates in
the vinylogous addition to C=X bonds,[8d,10] we herein
present the first uncatalyzed aqueous and solvent-free
three-component vinylogous Mukaiyama–Mannich re-
action (VMMnR) employing a pyrrole ketene silyl-
N,O-acetal, an aromatic amine, and diverse classes of
aldehydes. Two complementary protocols are estab-
lished, with which both hydrophobic aldehydes (aque-
ous and solvent-free conditions) and hydrophilic alde-
Keywords: catalyst-free conditions; green chemis-
try; Mukaiyama–Mannich reaction; synthetic meth-
ods; vinylogy; water
The development of enabling chemical methodologies hydes (aqueous conditions) operate, furnishing g-sub-
that fulfil such emblematic keywords as water, sol- stituted d-aminopyrrolinone units in high isolated
vent-free, environment awareness, atom economy, yields, with excellent levels of g-site selectivity and
and practicality is one of the greatest challenges of chemoselectivity, and moderate to high diastereose-
contemporary organic synthesis.[1] To this goal, several lectivity in favour of anti-configured adducts.
aqueous and solvent-free versions of leading carbon-
We initiated our journey by evaluating the one-pot
carbon bond-forming reactions have been successfully three-component VMMnR between N-Boc-protected
explored,[2] including the venerable Diels–Alder cy- trimethylsilyloxypyrrole (1a), 3-methylbutanal (2a),
cloaddition,[3] the aldol addition reaction,[4] the Man- and aniline (3a) in pure neutral water under vigorous
nich[5] and Michael couplings,[6] the Claisen rearrange- stirring at room temperature (Table 1, entry 1). Very
ment,[3b,7] to mention only a few.
poor amounts of the Mannich product 4a formed
after 10 h, which was accompanied by detectable
3278
ꢁ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2011, 353, 3278 – 3284

Aqueous and Solvent-Free Uncatalyzed Three-Component Vinylogous Mukaiyama–Mannich Reactions
Table 1. Primary screening results of uncatalyzed, three-component VMMnR of pyrrole silyl dienolates with 3-methylbutanal
and various primary amines.[a]
Entry
1: PG/SiR3
3: R
Reaction Medium
Product
Conversion [%][b]
dr (anti:syn)[c]
1[d]
2
3
4
5
6
7
8
1a: Boc/TMS
1a: Boc/TMS
1b: Boc/TBS
1c: Boc/TES
1d: Boc/TIPS
1e: Cbz/TBS
1f: Ts/TBS
1g: Bn/TBS
1b: Boc/TBS
1b: Boc/TBS
1b: Boc/TBS
1b: Boc/TBS
1b: Boc/TBS
1b: Boc/TBS
1b: Boc/TBS
1b: Boc/TBS
1b: Boc/TBS
1b: Boc/TBS
1b: Boc/TBS
1b: Boc/TBS
1b: Boc/TBS
1b: Boc/TBS
3a: C6H5
3a: C6H5
3a: C6H5
3a: C6H5
3a: C6H5
3a: C6H5
3a: C6H5
3a: C6H5
3a: C6H5
3a: C6H5
3a: C6H5
3a: C6H5
3a: C6H5
3a: C6H5
3b: o-MeOC6H4
3b: o-MeOC6H4
3b: o-MeOC6H4
3b: o-MeOC6H4
3c: p-MeOC6H4
3d: o-ClC6H4
3e: Bn
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
CH2Cl2
toluene
H2O
H2O
none
H2O
none
H2O
none
H2O
H2O
H2O
H2O
4a
4a
4a
4a
4a
4b
4c
4d
4a
4a
4a
4a
4a
4a
4e
4e
4e
4e
4f
4g
4h
4i
30 (21)
38 (27)
94 (82)
55 (43)
60 (54)
61 (49)
66 (58)
30 (22)
96 (80)
46 (38)
51 (42)
95 (83)
85 (75)
>99 (90)
>99 (95)
>99 (96)
82 (74)
52 (47)
43 (35)
60 (51)
<10
81:19
82:18
92:8
80:20
72:28
83:17
85:15
85:15
92:8
72:28
78:22
92:8
92:8
93:7
9[e]
10
11
12[f]
13[g]
14
15
16
17[d]
18[d]
19
20
21
22
93:7
92:8
88:12
88:12
88:12
72:28
nd
3f: i-C3H7
<10
nd
[a]
Unless otherwise noted, the following reaction conditions were used: pyrrole 1 (1.0 equiv., 0.4 mmol), aldehyde 2a
(1.0 equiv.), amine 3 (1.0 equiv.), reaction medium (100 equiv.), at 30Æ28C for 10 h under 59 KHz ultrasonic irradiation.
[b]
1
Determined by H NMR analysis of the crude reaction products; values in parentheses refer to combined yields of isolat-
ed products.
[c]
[d]
[e]
[f]
1
Determined by H NMR analysis of the reaction crude; nd=not determined.
At room temperature, under magnetic stirring (400 rpm), no sonication used.
Reaction time, 24 h.
10 equiv. water were used.
1.0 equiv. water was used.
[g]
quantities of the corresponding g-aldol addition by- creased performance (entries 4–8), while variation of
product. Application of ultrasonic irradiation was the reaction time led to no significant improvement
equally disappointing, resulting in moderate produc- (entry 9). In comparison, uncatalyzed VMMnR in an-
tion of 4a and substantial recovery of the hydrolyzed hydrous CH2Cl2 or toluene proved scantily produc-
N-Boc-pyrrolinone product (entry 2). We assumed tive, giving rise to aminated lactam 4a in only moder-
that these unfavourable results were mainly due to ate yield with ca. 70:30 anti:syn diastereomeric ratio
competition of the aldol reaction and, especially, to (entries 10 and 11).
the lability of the delicate TMS-pyrrole 1a to water.
Therefore, we turned our attention to more robust N- dient for the reaction to occur; thus, the next experi-
Boc-protected TBS-pyrrole 1b (entry 3). ments focused on evaluating the effect of the water
Actually, water appeared to be an important ingre-
After 10 h sonication at 308C, we were pleased to content within the three-component reactant mixture.
find that the crude material solely consisted of the ex- Diminishing the water content from 100 mol equiv. to
pected Mannich product 4a, which was isolated in 10 mol equiv. did not prove detrimental, and further
82% yield (94% conversion), as a 92:8 mixture of reduction to 1.0 mol equiv. did not cause significant
anti- and syn-configured isomers.
erosion of the good reaction performance displayed
Evaluation of other pyrrole candidates bearing dif- with 100 mol equiv. water (entries 12 and 13 vs.
ferent nitrogen and silicon substituents resulted in de- entry 3).
Adv. Synth. Catal. 2011, 353, 3278 – 3284
ꢁ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
3279

Andrea Sartori et al.
COMMUNICATIONS
At this juncture, we opted to abolish water all to- products 4e, 5b–5d in good to excellent isolated
gether (entry 14) and, rather unexpectedly, by simply yields, with virtually complete g-site selectivity and no
irradiating a mixture of 1.0 equiv. each of pyrrole 1b, side products. Consistent preference for the anti-con-
isovaleraldehyde (2a), and aniline (3a) at 308C for figured adducts was attained, with dr values ranging
10 h, adduct 4a formed in high yield and with an ex- from 91:9 to 98:2. Neutral, electron-rich, and elec-
cellent 93:7 dr in favour of the anti-isomer.
tron-poor aromatic aldehydes also proved to be perti-
With both aqueous and solvent-free reaction alter- nent substrates (entries 5–8), which furnished the ex-
natives almost equally viable, our further scrutiny in- pected Mannich adducts in good isolated yields for
volved the applicability of these VMMnR procedures both W and SF reaction conditions. However, with
with respect to the amine component, again employ- these aldehydes the diastereoselectivity was markedly
ing pyrrole 1b and aldehyde 1a. Success was attained lower than that obtained with aliphatic counterparts.
with o-anisidine (3b), with the solvent-free protocol W and SF protocols were particularly suited for pro-
performing equally well as compared to the corre- tected alkoxy aldehydes (entries 9 and 10), leading to
sponding aqueous counterpart (entries 15 vs. 16).[11] the products with promising yields and complete g-
Also, p-anisidine (3c) and o-chloroaniline (3d) were site selectivities. Remarkably, with protected (R)-glyc-
tolerated, albeit with inferior results (entries 19 and eraldehyde 2j three stereoisomers were obtained, the
20). Interestingly, aliphatic candidates such as benzyl- major product being the 5,1’-anti:1’,2’-anti-configured
amine (3e) and isopropylamine (3f) proved ineffec- isomer 5j, which was accompanied by the 5,1’-
tive (entries 21 and 22), highlighting the unique role anti:1’,2’-syn isomer 5j’ and the 5,1’-syn:1’2’-syn
displayed by anilines in these uncatalyzed transforma- isomer 5j’’ with 3/2.8/1 (W) and 2/1.6/1 (SF) diastereo-
tions. Collectively, these data suggest that the combi- meric ratios for the three candidates. In this special
nation of Boc and TBS substituents within the pyrrole case the magnitude of the simple diastereoselection
donor 1 provided the optimum balance between reac- favouring the 5,1’-anti isomers is maintained
tivity, selectivity, and stability, with o-anisidine pre- (anti:syn=85:15 and 78:22 for the W and SF proto-
ferred as the amine component.[12] Not only is o-anisi- cols, respectively), whereas the facial selectivity at the
dine less toxic than aniline itself and relatively inex- aldehyde carbonyl is low in both cases (1’,2’-syn:anti
pensive, it is also easy to remove when the Mannich ratio=56:44), demonstrating that the presence of the
products have to be advanced to further synthetic ma- chiral a-alkoxy group is not a prerequisite for deter-
nipulation.[13] Also, the ortho-substitution provided by mining the sense of the diastereofacial selectivity of
2-anisidine, in conjunction with the presence of water, these reactions.
might concur to activate the imine via an H-bridge
bond in the setting of a chelate with the methoxy hyde (2k) (37% formalin), dimethoxyacetaldehyde
group. (2l) (60% in water), and chloroacetaldehyde (2m)
Highly hydrophilic substrates, namely formalde-
Following on from these primary screening studies (55% in water), which are commercially available as
and capitalizing on the above findings, we went on to solutions in water, were obviously assayed with the W
investigate the scope of the present VMMnR in terms protocol only (entries 11–13). To our delight, the
of the aldehyde component. Although it may well be Mannich products could be acquired smoothly in ex-
that specific optimization would be necessary for each cellent yields, with virtually complete g-selectivity and
aldehyde to optimize both the efficiency and selectivi- favourable dr values in favour of anti-isomers. Per-
ty of the processes, all VMMnR were carried out haps most notable, protecting group-free, racemic
using N-Boc-TBS-substituted pyrrole 1b and o-anisi- glyceraldehyde 2n reacted efficiently (entry 14), and
dine (3b) under the conditions optimized for aldehyde again we were happy to see that the expected vinylo-
2a (see entries 15 and 16 in Table 1). As can be seen, gous Mannich compounds 5n, 5n’ and 5n’’ still formed
in addition to isovaleraldehyde (2a) used in the initial in satisfactory 61% combined yield, to which 5,1’-
investigation, which furnished adduct 4e, both lipo- anti:1’,2’-syn, 5,1’-anti:1’,2’-anti-, and 5,1’-syn:1’,2’-syn-
philic and hydrophilic aldehydes were scrutinized. configurations were assigned, respectively, based on
Aqueous (W) and solvent-free (SF) protocols were chemical correlation to the enantiopure materials pre-
adopted in parallel and the results are grouped in viously obtained with protected (R)-glyceraldehyde 2j
Table 2.
The palette of scrutinized aldehydes encompassed
(entry 14 vs. 10).
The relative configuration within isovaleraldehyde-
aliphatic aldehydes 2a–2d, aromatic representatives derived adduct anti-4e and the relative (hence abso-
2e–2h, suitably protected a-alkoxy aldehydes 2i and lute) configuration within glyceraldehyde-derived
2j, as well as hydrophilic candidates 2k–2n. All the compounds 5j’ (via its saturated counterpart 6) and
lipophilic aliphatic aldehydes (entries 1–4) reacted 5j’’ were unambiguously established by single crystal
with almost equal ease when both aqueous (plain en- X-ray diffraction analyses (Figure 1), whilst the struc-
tries) and solvent-free (primed entries) methodologies tures of the remaining Mannich adducts were as-
were applied, and delivered the expected Mannich
3280
asc.wiley-vch.de
ꢁ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2011, 353, 3278 – 3284

Aqueous and Solvent-Free Uncatalyzed Three-Component Vinylogous Mukaiyama–Mannich Reactions
Table 2. Scope of aldehydes for the uncatalyzed three-component VMMnR under aqueous (W) and solvent-free (SF) condi-
tions.[a]
Entry
2: R
Conditions
Time [h]
Product
Yield [%][b]
dr (anti:syn)[c]
1
1’
2
2’
3
3’
4
4’
5
5’
6
6’
7
7’
8
2a: i-Bu
W
SF
W
SF
W
SF
W
SF
W
SF
W
SF
W
SF
W
SF
W
SF
9
8
9
7
7
6
8
6
7
7
7
9
9
8
20
8
21
13
4e
95
96
82
99
96
99
83
95
82
71
91
87
94
78
60
83
72
91
93:7
92:8
94:6
93:7
98:2
96:4
93:7
91:9
67:33
67:33
61:39
57:43
65:35
61:39
73:27
62:38
99:1
2b: i-Pr
5b
5c
5d
5e
5f
5g
5h
5i
2c: c-hexyl
2d: n-heptyl
2e: C6H5
2f: p-MeOC6H4
2g: p-BrC6H4
2h: p-NO2C6H4
8’
9
9’
À
2i: CH2OTBS
98:2
10
W
14
5j
95
85:15[d]
10’
11
12
13
SF
W
W
W
8
5
13
7
96
99
92
91
78:22[e]
-
91:9
91:9
2k: H
5k
5l
5m
À
2 L: CH
(OMe)2
À
2m: CH2Cl
14
W
15
5n
61
90:10[f]
[a]
Unless otherwise noted, the following reaction conditions were used: pyrrole 1b (1.0 equiv., 0.4 mmol), aldehyde 2a–2n
(1.0 equiv.), amine 3b (1.0 equiv.), H2O (100 equiv.) (labelled as W) or neat (labelled as SF), at 30Æ28C under 59 KHz ul-
trasonic irradiation.
[b]
[c]
Combined yield of isolated products.
1
Determined by H NMR analysis of the reaction crude. Relative configurations anti:syn refer to the stereodisposition of
the newly formed C-5 and C-1’ stereocenters.
[d]
[e]
[f]
3/2.8/1 dr for the 5,1’-anti:1’,2’-anti-, 5,1’-anti:1’,2’-syn-, and 5,1’-syn:1’,2’-syn-configured isomers 5j, 5j’, and 5j’’.
2/1.6/1 dr for the 5,1’-anti:1’,2’-anti-, 5,1’-anti:1’,2’-syn-, and 5,1’-syn:1’,2’-syn-configured isomers 5j, 5j’, and 5j’’.
5.6/3/1 dr for the 5,1’-anti:1’,2’-syn-, 5,1’-anti:1’,2’-anti-, and 5,1’-syn:1’,2’-syn-configured isomers 5n, 5n’, and 5n’’.
signed by analogy or by comparison with known sub- arabinose (7) to pyrrole 1b and o-anisidine (3b) in the
stances (see the Supporting Information for details). presence of 100 mol equiv. water under ultrasonic ir-
Encouraged by the success of the aqueous protocol radiation did produce the expected C-glycosylated
with highly hydrophilic candidates, we finally won- lactam adducts in acceptable yield and diastereoselec-
dered to see whether protecting group-free aldose tivity (Scheme 1).
sugars could even be pertinent substrates in these
However, due to difficult purification of the crude
VMMnR trasformations. Remarkably, as was the case water-soluble material by chromatography, peracety-
with prototypical protecting group-free glyceralde- lation was necessary to arrive at pure pyrrolinone tet-
hyde 2n, direct exposure of commercial grade d-(À)- raacetate 8, which was delivered in 38% yield after
Adv. Synth. Catal. 2011, 353, 3278 – 3284
ꢁ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
3281

Andrea Sartori et al.
COMMUNICATIONS
Figure 1. ORTEP representation of the X-ray crystal structures of (Æ)-anti-4e (CCDC 834892), 5j’’ (CCDC 834893), 6
(CCDC 834894), and 8 (CCDC 834895) (see the Supporting Information for details). These data can be obtained free of
charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
Scheme 1. Water-assisted, three-component VMMnR as applied to protecting group-free d-arabinose 7.
chromatography (two steps). To this compound a 5,1’- versely, addition of as little as 1.0 mol equiv. of water
anti:1’,2’-syn-configuration (d-glycero-d-gulo) was as- propelled the reaction well, paralleling the results of
signed based on single crystal X-ray analysis the corresponding three-component reactions almost
(Figure 1).
exactly (see entries 1, 1’ in Table 2). Thus, water
Coming back to the role of water in the present seems to be a crucial element in both water and sol-
three-component vinylogous Mannich transformation, vent-free reactions and its role is manifold.
one may question as to whether and how water is
considered an active, indispensable reaction ingredi- VMMnR is hard to formulate, we can hypothesize
ent in these transformations. that water acts as both proton donor, to activate the
Even though a full rationale of the present
In truth, water is present even in reactions carried in situ-generated imine component, and silicon scav-
out under neat conditions (1.0 equiv., that is, the alde- enger, to sequestrate the silicon ion into an inactive
hyde-amine condensation by-product), and only R3SiOH species, which is actually the sole by-product
subtle variation of yield and selectivity is observed in these transformations. Other peculiar functions of
when passing from aqueous to solvent-free experi- water as transition state stabilizer or ion species-sol-
ments.
vating agent cannot in principle be ruled out, while
To exclude water completely, we assayed a two- the often invoked paradigm of the hydrophobic effect
component VMMnR using a preformed, pure imine, or cohesive pressure effect exerted by water under
keeping the environment as anhydrous as possible. water conditions[14] hardly applies in this special case,
When pyrrole 1b was exposed to the imine derived owing to the close parallelism observed for both
from aldehyde 2a and amine 3b under an argon at- aqueous and solvent-free experimentations.[15]
mosphere, no reaction occurred at all, and complete
In conclusion, we have developed an unprecedent-
recovery of the starting reactants was attained. Con- ed three-component vinylogous Mukaiyama–Man-
3282
asc.wiley-vch.de
ꢁ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2011, 353, 3278 – 3284

Aqueous and Solvent-Free Uncatalyzed Three-Component Vinylogous Mukaiyama–Mannich Reactions
The anti/syn diastereomeric ratio of the products was deter-
mined to be 92:8 by H NMR analysis of the crude reaction
residue. The crude residue was then purified by silica gel
flash chromatography (hexane/EtOAc 70/30) affording anti-
4e (yield: 127 mg) as a white solid and syn-4e (<ield:
11 mg) as a colourless oil in a 96% combined yield.
nich-type methodology amenable to work equally
well under both aqueous and solvent-free environ-
ments. No catalysts, salts, organic solvents, co-sol-
vents, surfactants, or metal adjuvants are required.[16]
Thanks to its operational simplicity and practicality,
this unique transformation allows the expedient for-
mation of a repertoire of valuable vicinal aminolac-
tam structures in high isolated yields, with virtually
complete g-site selectivities, good diastereoselectivi-
ties in favour of the anti-configured adducts, and no
aldol by-products. A varied palette of lipophilic alde-
hyde substrates carrying diverse aliphatic and aromat-
ic substituents is well suited, as are highly hydrophilic
candidates which are available solely as solutions in
water. The power of this technology is particularly
evident when applied to protecting group-free, sugar-
related carbonyls, which paves the way to the con-
struction of a rare progeny of chiral non-racemic pyr-
rolinone C-glycoside frameworks with good stereo-
control.
1
Supporting Information
Description of experimental procedures, characterization
data, crystal data for compounds (Æ)-anti-4e, 5j’’, 6, and 8,
transition state models, and NMR spectra of new com-
pounds are available as Supporting Information.
Acknowledgements
Funding from Universitꢀ degli Studi di Parma is gratefully
acknowledged. The authors thank the Centro Interdiparti-
mentale Misure “G. Casnati” (Universitꢀ degli Sudi di
Parma) for instrumental facilities and Alessia Zanichelli for
preliminary experiments.
Experimental Section
References
Representative Experimental Procedure W (Aqueous
Conditions): Preparation of Lactam anti-4e
[1] a) R. Breslow, in: Green Chemistry, (Eds.: P. T. Anastas,
T. C. Williamson), Oxford University Press, New York,
1998, p 225; b) J. O. Metzger, Angew. Chem. 1998, 110,
3145–3148; Angew. Chem. Int. Ed. 1998, 37, 2975–2978;
c) K. Tanaka, F. Toda, Chem. Rev. 2000, 100, 1025–
1074; d) R. A. Sheldon, Green Chem. 2005, 7, 267–278;
e) P. J. Walsh, H. Li, C. Anaya de Parrodi, Chem. Rev.
2007, 107, 2503–2545.
[2] a) A. Lubineau, J. Augꢃ, Y. Queneau, Synthesis 1994,
741–760; b) J. B. F. N. Engberts, B. L. Feringa, E.
Keller, S. Otto, Recl. Trav. Chim. Pays-Bas 1996, 115,
457–464; c) J. Mlynarski, J. Paradowska, Chem. Soc.
Rev. 2008, 37, 1502–1511; d) C. Pan, Z. Wang, Coord.
Chem. Rev. 2008, 252, 736–750; e) J. Paradowska, M.
Stodulski, J. Mlynarski, Angew. Chem. 2009, 121, 4352–
4362; Angew. Chem. Int. Ed. 2009, 48, 4288–4297; f) M.
Raj, V. K. Singh, Chem. Commun. 2009, 6687–6703;
g) N. Mase, C. F. Barbas III, Org. Biomol. Chem. 2010,
8, 4043–4050.
[3] a) D. C. Rideout, R. Breslow, J. Am. Chem. Soc. 1980,
102, 7816–7817; b) S. Narayan, J. Muldoon, M. G. Finn,
V. V. Fokin, H. C. Kolb, K. B. Sharpless, Angew. Chem.
2005, 117, 3275–3279; Angew. Chem. Int. Ed. 2005, 44,
3157–3161; c) A. B. Northrup, D. W. C. MacMillan, J.
Am. Chem. Soc. 2002, 124, 2458–2460; d) C. Loncaric,
K. Manabe, S. Kobayashi, Adv. Synth. Catal. 2003, 345,
475–477; e) M. Lemay, L. Aumand, W. W. Ogilvie, Adv.
Synth. Catal. 2007, 349, 441–447; f) D.-Q. Xu, A.-B.
Xia, S.-P. Luo, J. Tang, S. Zhang, J.-R. Jiang, Z.-Y. Xu,
Angew. Chem. 2009, 121, 3879–3882; Angew. Chem.
Int. Ed. 2009, 48, 3821–3824.
N-(tert-Butoxycarbonyl)-2-[(tert-butyldimethylsilyl)oxy]pyr-
role (TBSOP, 1b) (114.3 mg, 0.384 mmol) was added to the
heterogeneous mixture of isovaleraldehyde (2a) (41 mL,
0.384 mmol), o-anisidine (3b) (43 mL, 0.384 mmol) and
water (692 mL, 38.4 mmol) and kept under sonication in an
open-air vessel. The resulting heterogeneous reaction mix-
ture was kept in the ultrasound bath at ca. 308C and moni-
tored by TLC (hexane/EtOAc 70/30) to check the complete
disappearance of the reactants. After 9 h, the reaction was
judged complete and the reaction mixture was extracted
with EtOAc (3ꢂ1 mL). The organic layers were collected,
dried with MgSO4, filtered, and concentrated under vacuum
to give a mixture of anti/syn-4e. The anti/syn diastereomeric
1
ratio of the products was determined to be 93:7 by H NMR
analysis of the crude reaction residue. The residue was then
purified by silica gel flash chromatography (hexane/EtOAc
70/30) affording anti-4e (yield: 127 mg) as a white solid and
syn-4e (yield: 9.6 mg) as a colourless oil in a 95% combined
yield. Characterization data and crystal data are given in the
Supporting Information.
Representative Experimental Procedure SF (Solvent-
Free Conditions): Preparation of Lactam anti-4e
Pyrrole 1b (114.3 mg, 0.384 mmol) was added to the mixture
of isovaleraldehyde (2a) (41 mL, 0.384 mmol), and o-anisi-
dine (3b) (43 mL, 0.384 mmol) in an open-air vessel kept
under sonication. The reaction was sonicated at ca. 308C
and monitored by TLC (hexane/EtOAc 70/30) to check the
complete disappearance of the reactants. The reaction was
judged complete after 8 h and the reaction mixture was con-
centrated under reduced pressure to remove volatile by-
products (e.g., TBSOH) obtaining a mixture of anti/syn-4e.
[4] a) A. Lubineau, E. Meyer, Tetrahedron 1988, 44, 6065–
6070; b) T. J. Dickerson, T. Lovell, M. M. Meijler, L.
Noodleman, K. D. Janda, J. Org. Chem. 2004, 69, 6603–
6609; c) S. Aratake, T. Itoh, T. Usui, M. Shoji, Y. Haya-
Adv. Synth. Catal. 2011, 353, 3278 – 3284
ꢁ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
3283

Andrea Sartori et al.
COMMUNICATIONS
shi, Chem. Commun. 2007, 2524–2526; d) F. Giacalone,
M. Gruttadauria, P. Lo Meo, S. Riela, R. Noto, Adv.
Synth. Catal. 2008, 350, 2747–2760; e) S. S. V. Ramasas-
try, K. Albertshofer, N. Utsumi, C. F. Barbas III, Org.
Lett. 2008, 10, 1621–1624; f) M.-K. Zhu, X.-Y. Xu, L.-
Z. Gong, Adv. Synth. Catal. 2008, 350, 1390–1396; g) C.
Curti, L. Battistini, F. Zanardi, G. Rassu, V. Zambrano,
L. Pinna, G. Casiraghi, J. Org. Chem. 2010, 75, 8681–
8684; h) S. Pedatella, M. De Nisco, D. Mastroianni, D.
Naviglio, A. Nucci, R. Caputo, Adv. Synth. Catal. 2011,
353, 1443–1446.
Kempf, J. Org. Chem. 2002, 67, 5445–5453; f) B. Dudot,
A. Chiaroni, J. Royer, Tetrahedron Lett. 2000, 41, 6355–
6359, corrigendum 2000, 41, 8667.
[10] G. Casiraghi, F. Zanardi, L. Battistini, G. Rassu, Synlett
2009, 1525–1542.
[11] Ultrasound seems to impact the behaviour of the pres-
ent VMMnR coupling, improving reaction rates, prod-
uct yields, and diastereoselectivity as well (see en-
tries 15 and 16 vs. 17 and 18 in Table 1). This forces us
to assume that the effect of sonication is not merely
mechanical, but involves alteration of the product dis-
tribution. For a seminal review on ultrasound in syn-
thetic organic chemistry, see: T. J. Mason, Chem. Soc.
Rev. 1997, 26, 443–451.
[12] Three-component VMMnR additions to iminium ions
formed in situ from aldehydes and secondary amines
were also investigated under both aqueous and solvent-
free conditions. In the absence of any catalyst, reaction
between 1b, 2a, and N-methylaniline provided the re-
spective addition products in modest yields and re-
duced diastereoselectivities (55% yield, 83:27 dr, and
18% yield, 67:33 dr for aqueous and solvent-free condi-
tions, respectively). In comparison, non-aromatic repre-
sentatives such as morpholine and dibenzylamine
proved totally reluctant to react.
[13] a) J. F. Traverse, A. H. Hoveyda, M. L. Snapper, Org.
Lett. 2003, 5, 3273–3275; b) N. S. Josephsohn, E. L.
Carswell, M. L. Snapper, A. H. Hoveyda, Org. Lett.
2005, 7, 2711–2713; c) J. M. M. Verkade, L. J. C. van
Hermert, P. J. L. M. Quaedflieg, P. L. Alsters, F. L. van
Delft, F. P. J. T. Rutjes, Tetrahedron Lett. 2006, 47,
8109–8113.
[14] a) Organic Reactions in Water: Principles, Strategies
and Applications, 1st edn., (Ed.: U. M. Lindstrçm),
Blackwell Publishing, Oxford, 2007; b) M. C. Pirrung,
K. Das Sarma, J. Wang, J. Org. Chem. 2008, 73, 8723–
8730; c) A. Chanda, V. V. Fokin, Chem. Rev. 2009, 109,
725–748; d) R. N. Butler, A. G. Coyne, Chem. Rev.
2010, 110, 6302–6337.
[15] Due to Z/E geometric equilibration, imines can adopt
syn- or anti-disposed arrangements in the transition
states, and this renders a precise mechanistic rationale
accounting for the observed diastereoselection hard to
formulate. Nevertheless, based on several precedents in
this field, plausible transition states for the present
anti-selective VMMnR of N-arylimines to silyloxypir-
roles are visualized in Figure S1 in the Supporting In-
formation.
[16] As a genuinely green option, products of entries 1, 1’,
2’, 3, 3’, 4’, 9’, and 11 in Table 2 can be isolated directly
by high vacuum treatment of the reaction crudes, thus
avoiding organic solvent intervention. However, for the
data to be consistent, standard protocols involving or-
ganic solvents and chromatography were adopted in all
experiments.
[5] a) C. Loncaric, K. Manabe, S. Kobayashi, Adv. Synth.
Catal. 2003, 345, 1187–1189; b) L. Cheng, X. Wu, Y.
Lu, Org. Biomol. Chem. 2007, 5, 1018–1020; c) Y. Hay-
ashi, T. Urushima, S. Aratake, T. Okano, K. Obi, Org.
Lett. 2008, 10, 21–24; d) R. H. Qiu, S. F. Yin, X. W.
Zhang, J. Xia, X. H. Xu, S. L. Luo, Chem. Commun.
2009, 4759–4761; e) N. Azizi, F. Ebrahimi, M. R. Saidi,
Trans. C: Chem. Chem. Eng. 2009, 16, 94–98, and refer-
ences cited therein.
[6] a) A. Carlone, M. Marigo, C. North, A. Landa, K. A.
Jørgensen, Chem. Commun. 2006, 4928–4930; b) D. Co-
quiꢄre, B. L. Feringa, G. Roelfes, Angew. Chem. 2007,
119, 9468–9471; Angew. Chem. Int. Ed. 2007, 46, 9308–
9311; c) B. Tan, X. F. Zeng, Y. P. Lu, P. J. Chua, G. F.
Zhong, Org. Lett. 2009, 11, 1927–1930; d) Z. L. Zheng,
B. L. Perkins, B. K. Ni, J. Am. Chem. Soc. 2010, 132,
´
50–51; e) M. Rogozinska, A. Adamkiewicz, J. Mlynar-
ski, Green Chem. 2011, 13, 1155–1157.
[7] a) E. Brandes, P. A. Grieco, J. J. Gajewski, J. Org.
Chem. 1989, 54, 515–516; b) A. Lubineau, J. Augꢃ, N.
Bellanger, S. Caillebourdin, J. Chem. Soc. Perkin Trans.
1 1992, 1631–1636; c) M. P. Repasky, C. R. W. Guimar-
aes, J. Chandrasekhar, J. Tirado-Rives, W. L. Jorgensen,
J. Am. Chem. Soc. 2003, 125, 6663–6672; d) O. Aceve-
do, K. Armacost, J. Am. Chem. Soc. 2010, 132, 1966–
1975.
[8] For leading review articles, see: a) G. Casiraghi, F. Za-
nardi, G. Appendino, G. Rassu, Chem. Rev. 2000, 100,
1929–1972; b) S. K. Bur, S. F. Martin, Tetrahedron 2001,
57, 3221–3242; c) S. F. Martin, Acc. Chem. Res. 2002,
35, 895–904; d) G. Casiraghi, L. Battistini, C. Curti, G.
Rassu, F. Zanardi, Chem. Rev. 2011, 111, 3076–3154.
[9] For selected examples on Mukaiyama-type vinylogous
Mannich additions to imines in organic solvents, see:
a) Y. Yang, D. P. Phillips, S. Pan, Tetrahedron Lett.
2011, 52, 1549–1552; b) S.-T. Ruan, J.-M. Luo, Y. Du,
P.-Q. Huang, Org. Lett. 2011, 13, 4938–4941; c) D. M.
Barnes, L. Bhagavatula, J. DeMattei, A. Gupta, D. R.
Hill, S. Manna, M. A. McLaughlin, P. Nichols, R. Pre-
mchandran, M. W. Rasmussen, Z. Tian, S. J. Witten-
berger, Tetrahedron: Asymmetry 2003, 14, 3541–3551;
d) D. M. Barnes, M. A. McLaughlin, T. Oie, M. W. Ras-
mussen, K. D. Stewart, S. J. Wittenberger, Org. Lett.
2002, 4, 1427–1430; e) D. A. DeGoey, H.-J. Chen, W. J.
Flosi, D. J. Grampovnik, C. M. Yeung, L. L. Klein, D. J.
3284
asc.wiley-vch.de
ꢁ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2011, 353, 3278 – 3284