A novel three-component [3+2] cycloannulation process for the rapid and highly stereoselective synthesis of pyrrolobenzoxazoles

Article abstract of DOI:10.1002/chem.201200405

A novel three-component, one-pot [3+2] cycloannulation process is reported that gives previously unknown tetrahydropyrrolo [2,1-b]benzoxazoles in good yields and generates four new σ bonds and two new stereogenic centers with excellent diastereoselectivity. The reaction of bissilyldienediolate with imine in aqueous CH₃CN in the presence of various Lewis acids is examined. The relative configuration of tetrahydropyrrolo [2,1-b] benzoxazole show that benzoxazole forms a vaulted structure with both phenyl and ester substituents located on the convex face of the molecule, which most likely represents the thermodynamically favorable configuration. The three-component reaction of benzaldehyde, 2-aminophenol, and the nucleophile in CHCl₃ in the presence of Sc(OTf)₃ and the chiral N,N'-dioxide ligand with subsequent addition of tetra-n-butylammonium fluoride (TBAF) in CH ₃CN/H₂O gave product 3a in excellent yield and 81% enantiomeric excess.

Full text of DOI:10.1002/chem.201200405

COMMUNICATION
DOI: 10.1002/chem.201200405
A Novel Three-Component [3+2] Cycloannulation Process for the Rapid and
Highly Stereoselective Synthesis of Pyrrolobenzoxazoles
Michael Boomhoff and Christoph Schneider*[a]
Dedicated to Professor Lutz F. Tietze on the occasion of his 70th birthday
The rapid assembly of novel heterocyclic scaffolds is an
important and currently intensely investigated research
topic primarily in the light of its relevance to medicinal
chemistry.[1] In particular, domino reactions that lead to mul-
tiple bond-forming events in a one-pot operation are highly
attractive processes due to their flexibility, operational sim-
plicity, and reaction efficiency.[2] Ideally, such processes are
accompanied by the generation of new reactive functional
groups and full stereochemical control over newly formed
stereogenic centers.
nylketene silyl O,O-acetal could further extend this reaction
pathway. Under acidic aqueous reaction conditions the vi-
nylogous Mannich product should in principle undergo hy-
drolytic cleavage of the newly formed silyl enol ether to
give a highly reactive a-keto ester, which in turn could
engage the previously formed amine in concert with a suita-
ble secondary nucleophile in a cyclocondensation reaction
generating an N,O-acetal spontaneously (Scheme 1). Ac-
The pyrrolidine motif is among the most important
heteroACHTUNGTRENNUNGcyclic ring systems and can be found in numerous bio-
logically active natural products, pharmaceuticals, and agro-
chemicals.[3] In addition, pyrrolidines may be attached to
other heterocyclic rings to give fused heterocycles, such as
those found, for example, in pyrroloindoline, pyrrolobenzo-
diazepine, and pyrroloisoquinoline alkaloids.[4] Standard
methodology to access the pyrrolidine ring system in
a direct manner is mainly based upon [3+2] cycloaddition
processes, namely azomethine ylide–alkene,[5] trimethylene-
methane–imine,[6] and allene–imine cycloadditions.[7] In addi-
tion, [3+2] annulation reactions of imines with allylsilanes[8]
and cyclopropane derivatives[9] have been developed.
Scheme 1. Envisioned strategy.
We report, herein, a novel three-component, one-pot
[3+2] cycloannulation process that gives previously un-
known tetrahydropyrrolo [2,1-b]benzoxazoles in good yields
and generates four new s bonds and two new stereogenic
centers with excellent diastereoselectivity.[10] Moreover, we
demonstrate that this process can be rendered enantioselec-
tive with a suitable chiral scandium catalyst.
We have recently developed the Brønsted acid catalyzed,
enantioselective, vinylogous Mannich reaction of acyclic vi-
nylketene silyl-O,O-acetals that gives rise to functionalized
d-amino a,b-unsaturated esters in high yields and good-to-
excellent enantio- and diastereoselectivities.[11] We reasoned
that an additional silyloxy group in the 2-position of the vi-
cordingly, the envisioned bissilyldienediolate 1 would for-
mally constitute the equivalent of an a-keto ester homoeno-
late and react as a 1,3-zwitterionic synthon at the same
time.[12] Johnson and co-workers recently reported aldol re-
actions of in situ formed metallodienediolates of the same
type as 1, but observed opposite a-regioselectivity as
a result of the different atomic orbital coefficients in metal
versus silyl-containing dienolates.[13] In addition, Marsden
et al. employed a related bimetaldienediolate in highly a-re-
gioselective alkylation reactions.[14]
We initiated our study by examining the reaction of bissi-
lyldienediolate 1 with imine 2a in aqueous CH3CN in the
presence of various Lewis acids (see Table 1 for a selec-
tion).[15] Among the Lewis acids screened, Yb
ACHTUNGTRENNUNG
ZnACHTUGNTRENNNUG
[a] M. Boomhoff, Prof. Dr. C. Schneider
Institut fꢀr Organische Chemie
Universitꢁt Leipzig
tetrahydropyrrolo [2,1-b] benzoxazole 3a as a single diaste-
reomer in good yields of up to 82% within 48 h (Table 1, en-
tries 4 and 7). The reaction time could be significantly re-
duced by increasing the amount of water employed. Thus,
Johannisallee 29
D-04103 Leipzig (Germany)
E-mail: schneider@chemie.uni-leipzig.de
with 20 mol% of YbACTHNUTRGNEUNG(OTf)3 in CH3CN/water solvent (9:1)
the reaction was completed within 3 h and delivered 3a in
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201200405.
Chem. Eur. J. 2012, 18, 4185 – 4189
ꢂ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
4185

Table 1. Initial optimization studies.[a]
Entry
LA
(OTf)3
La(OTf)3
Sc(OTf)3
Yb(OTf)3
Cu(OTf)2
AgOTf
Zn(OTf)2
Yb(OTf)3
Zn(OTf)2
(OTf)3
(OTf)3
(OTf)3
(OTf)3
(OTf)3
t [h]
Yield [%][b]
1
2
3
4
5
6
7
Y
G
96
48
8.5
24
24
24
48
3.5
21
4.5
15
4
71
58
57
79
53
72
82
82
73
74
74
81
74
84
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
8[c]
9[c]
10[c,d]
11[c,e]
12[c,f]
13[c,g]
14[h]
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
Figure 1. Crystal structure of (rac)-3a.
Yb
Yb
Yb
Yb
Yb
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
Table 2. Scope of the [3+2] cycloannulation process.[a]
G
6.5
4
ACHTUNGTRENNUNG
[a] Reaction conditions (unless otherwise noted): imine 2a (1.0 equiv,
0.20 mmol), diene 1 (3.0 equiv), Lewis acid (20 mol%), H2O (5.0 equiv),
MeCN (2 mL). [b] Yield of isolated product as a single diastereomer.
[c] Reaction in MeCN/H2O 9:1 (2 mL). [d] YbACHTUNGTRENN(UNG OTf)3 (10 mol%).
[e] Yb(OTf)3 (1 mol%). [f] Diene 1 (2.0 equiv). [g] Diene 1 (1.2 equiv).
ACHTUNGTRENNUNG
[h] Three-component reaction: benzaldehyde (1.0 equiv, 1.30 mmol), 2-
aminophenol (1.0 equiv), diene 1 (2.0 equiv) in MeCN/H2O (9:1, 6.5 mL).
TMS=trimethylsilyl, LA=Lewis acid.
Entry
R1
R2
Product
t [h]
Yield [%][b]
1
2
3
4
5
6
7
8
Ph
H
H
H
H
H
H
H
H
H
H
H
H
H
3a
3b
3c
3d
3e
3 f
3g
3h
3i
4
3.5
4
4
2
1
3
4
1.5
2.5
4
5
3
84
64
75
78
73
87
71
62
75
84
79
75
58
4-MeOC6H4
4-MeC6H4
4-tBuC6H4
4-NO2C6H4
4-NCC6H4
4-FC6H4
4-ClC6H4
3-ClC6H4
2-ClC6H4
2-BrC6H4
2-naphthyl
2-thiophenyl
identical yield (Table 1, entry 8). This observation is consis-
tent with the assumption that hydrolysis of the silyl enol
ether represents the slow step of this stepwise process and is
further substantiated through detection of the initial vinylo-
gous Mannich product after 1–2 h in significant amounts.[16]
The catalyst loading could be reduced to only 1 mol% still
generating the product in 74% yield within 15 h (Table 1,
entries 10 and 11). Further investigations revealed that two
equivalents of the nucleophile 1 were sufficient to achieve
good results, whereas stoichiometric amounts gave rise to
lower yields (Table 1, entries 12 and 13). More importantly,
running the reaction in a three-component fashion with sep-
arate additions of benzaldehyde, 2-aminophenol, and nucle-
ophile and in situ imine formation gave rise to even slightly
improved results and isolation of isomerically pure 3a in
84% yield (Table 1, entry 14,). This protocol was therefore
employed for all further reactions.
9
10
11
12
13
3j
3k
3l
3m
14
H
3n
1
63
15
H
3o
3
56
16
17
18
19
20
tBu
cyclohexyl
Ph
Ph
Ph
H
H
Me
tBu
Cl
3p
3q
3r
3s
3t
3
2.5
4
3.5
4
76
70
63
70
62
The relative configuration of tetrahydropyrrolo [2,1-b]
benzoxazole 3a was unambiguously determined by X-ray
crystallography.[17] As shown in Figure 1, benzoxazole 3a
forms a vaulted structure with both phenyl and ester sub-
stituents located on the convex face of the molecule, which
most likely represents the thermodynamically favorable con-
figuration.
Under the optimal reaction conditions, a variety of differ-
ent aldehydes and 2-aminophenols were subsequently evalu-
ated in this process giving the desired products as single dia-
stereomers in generally good yields (Table 2). Aromatic al-
dehydes carrying both electron-donating and electron-with-
[a] Reaction conditions: aldehyde 4 (1.0 equiv, 1.30 mmol), 2-aminophe-
nol 5 (1.0 equiv), diene 1 (2.0 equiv), Yb(OTf)3 (20 mol%), MeCN/H2O
9:1 (6.5 mL). [b] Yield of isolated product.
AHCTUNGTRENNUNG
drawing groups, as well as heteroaromatic aldehydes, proved
to be good substrates. Moreover, different substitution pat-
terns were readily tolerated. In addition, aliphatic and unsa-
turated aldehydes smoothly underwent the reaction to
afford the desired tetrahydropyrroloACTHNUTRGNEUNG[2,1-b]benzoxazoles
3n–q in moderate-to-good yields (Table 2, entries 14–17).
Variation in the 2-aminophenol component was also possible
4186
www.chemeurj.org
ꢂ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2012, 18, 4185 – 4189

A Three-Component [3+2] Cycloannulation Process
COMMUNICATION
giving rise to products 3r–t in equally good yields (Table 2,
entries 18–20).
Being N,O-acetals, pyrrolobenzoxazoles 3 could easily be
converted into reactive iminium ions upon exposure to
Lewis acids and further reacted with various nucleophiles
(Scheme 2). Thus, treatment of 3a with BF3·Et2O, which
of the iminium ion. Through concomitant transesterification
with the liberated phenol, the bicyclic benzoxazinone 6 was
obtained directly. This lactone was easily saponified with
LiOH and further converted into methyl ester 7, which con-
stitutes an interesting proline derivative with a quaternary
chiral center. This overall scheme could successfully be ex-
tended to the addition of a silylketene O,O-acetal in a Mu-
kaiyama–Mannich reaction and to the hydride addition with
NaCNBH3, both of which occurred again with complete dia-
stereoselectivity and delivered bicyclic benzoxazinone 8 and
methyl ester 9 in good yields, respectively.
In an attempt to develop a catalytic, enantioselective pro-
cess for this novel [3+2] cycloannulation, we eventually
found a chiral scandium complex most suitable, which Feng
et al. had established for a broad range of carbon–carbon
bond-forming reactions.[19] Thus, the three-component reac-
tion of benzaldehyde (4a), 2-aminophenol (5a), and the nu-
cleophile 1 in CHCl3 in the presence of ScACTHUNTRGNE(NUG OTf)3 and the
chiral N,Nꢃ-dioxide ligand 10 (28 mol%) with subsequent
addition of tetra-n-butylammonium fluoride (TBAF) in
CH3CN/H2O gave product 3a in excellent yield and 81%
enantiomeric excess (ee) (Scheme 3). Here, in the interest of
conversion and enantioselectivity, the initial vinylogous
Mannich reaction was performed under non-aqueous condi-
tions, and desilylation and acetalization were effected subse-
quently through addition of TBAF. The corresponding
ortho-bromo derivative 3k was obtained likewise with
83% ee, and a crystal structure analysis revealed its absolute
configuration (see the Supporting Information).[20]
Scheme 2. a) BF3·Et2O (1.5 equiv), allyltrimethylsilane (2.5 equiv), 1 h,
RT, CH2Cl2. b) LiOH·H2O (5.0 equiv), 20 min, RT, THF/H2O/MeOH
(3:1:1). c) NaH (5.0 equiv), MeI (10.0 equiv), 20 min, 08C, DMF.
d) BF3·Et2O (1.5 equiv), ((1-ethoxyvinyl)oxy)trimethylsilane (2.0 equiv),
5 min, 608C, 1,4-dioxane. e) BF3·Et2O (3.0 equiv), NaCNBH3 (2.0 equiv),
15 h, ꢀ308C, THF. f) LiOH·H2O (2.0 equiv), 20 min, RT, THF/H2O/
MeOH (3:1:1). g) NaH (4.0 equiv), MeI (10.0 equiv), 15 min, 08C, DMF.
proved to be optimal in this respect, and allyltrimethylsilane
cleanly gave the allylated product 6 in quantitative yield as
a single trans-diastereomer according to the crystal structure
analysis (Figure 2).[18] Apparently, the phenyl group directs
the attack of the incoming nucleophile to the opposite face
Scheme 3. Catalytic, enantioselective reaction.
In conclusion, we have developed a novel Lewis acid cata-
lyzed, stepwise [3+2] cycloannulation process, which con-
verts bissilyldienediolate 1, aldehydes, and 2-aminophenols
directly into previously unknown tetrahydropyrrolo [2,1-b]
benzoxazoles 3 in typically good yields and complete diaste-
reoselectivity. On the basis of their N,O-acetal structure,
benzoxazoles 3 were shown to be highly valuable synthetic
intermediates with the potential to access proline derivatives
with a quaternary stereogenic center with full stereochemi-
Figure 2. Crystal structure of (rac)-6.
Chem. Eur. J. 2012, 18, 4185 – 4189
ꢂ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
4187

C. Schneider and M. Boomhoff
see: e) D. Antonow, D. E. Thurston, Chem. Rev. 2011, 111, 2815–
2864.
cal control. In addition, preliminary results document that
a catalytic, enantioselective process is feasible with a chiral
scandium catalyst, which gives products with currently up to
83% ee. Ongoing studies in our group are directed towards
improving the scope, enantioselectivity, and applicability of
this novel reaction.
[5] For recent reviews, see: a) C. Nꢅjera, J. M. Sansano, Angew. Chem.
2005, 117, 6428–6432; Angew. Chem. Int. Ed. 2005, 44, 6272–6276;
b) S. Husinec, V. Savic, Tetrahedron: Asymmetry 2005, 16, 2047–
2061; c) G. Pandey, P. Banerjee, S. R. Gadre, Chem. Rev. 2006, 106,
4484–4517; d) H. Pellissier, Tetrahedron 2007, 63, 3235–3285;
e) L. M. Stanley, M. P. Sibi, Chem. Rev. 2008, 108, 2887–2902; f) J.
Adrio, J. C. Cerretero, Chem. Commun. 2011, 47, 6784–6794.
[6] For representative examples, see: a) B. M. Trost, C. M. Marrs, J. Am.
Chem. Soc. 1993, 115, 6636–6645; d) S. Yamago, M. Nakamura,
X. Q. Wang, M. Yanagawa, S. Tokumitsu, E. Nakamura, J. Org.
Chem. 1998, 63, 1694–1703; e) B. M. Trost, S. M. Silverman, J. P.
Stambuli, J. Am. Chem. Soc. 2007, 129, 12398–12399; f) M. Kimura,
T. Tamaki, M. Nakata, K. Tohyama, Y. Tamaru, Angew. Chem. 2008,
120, 5887–5889; Angew. Chem. Int. Ed. 2008, 47, 5803–5805;
g) B. M. Trost, S. M. Silverman, J. Am. Chem. Soc. 2010, 132, 8238–
8240.
[7] For representative examples, see: a) Z. Xu, X. Lu, J. Org. Chem.
1998, 63, 5031–5041; b) N. Fleury-Brꢄgeot, L. Jean, P. Retailleau, A.
Marinetti, Tetrahedron 2007, 63, 11920–11927; f) Y.-Q. Fang, E. N.
Jacobsen, J. Am. Chem. Soc. 2008, 130, 5660–5661; g) N. Pinto, N.
Fleury-Brꢄgeot, A. Marinetti, Eur. J. Org. Chem. 2009, 146–151;
h) X. Han, F. Zhong, Y. Wang, Y. Lu, Angew. Chem. 2012, 124, 791–
794; Angew. Chem. Int. Ed. 2012, 51, 767–770.
Experimental Section
Synthesis of 3a: Benzaldehyde (138 mg, 1.30 mmol,
1.0 equiv) was added to a solution of YbACTHNURTGNENG(U OTf)3 (162 mg,
0.26 mmol, 20 mol%) and 2-aminophenol (142 mg,
1.30 mmol, 1.0 equiv) in MeCN/H2O (9:1, 0.2m). After
5 min, nucleophile 1 (714 mg, 2.60 mmol, 2.0 equiv) was
added. Stirring was continued for 4 h at RT, until full con-
version was indicated by TLC. The solvent was removed
under reduced pressure, and silica-gel chromatography
(hexane!hexane/diethyl ether 30:1) gave 3a as a white
solid (338 mg, 84%, single diastereomer, m.p. 1388C). Addi-
tional details and full characterization data of all new com-
pounds are provided in the Supporting Information.
[8] For representative examples, see: a) J. S. Panek, N. F. Jain, J. Org.
Chem. 1994, 59, 2674–2675; b) T. Akiyama, M. Sugano, H. Kagoshi-
ma, Tetrahedron Lett. 2001, 42, 3889–3892; c) P. Restorp, A. Fischer,
P. Somfai, J. Am. Chem. Soc. 2006, 128, 12646–12647; d) P. Restorp,
M. Dressel, P. Somfai, Synthesis 2007, 1576–1583; e) M. Dressel, P.
Restorp, P. Somfai, Chem. Eur. J. 2008, 14, 3072–3077.
Acknowledgements
[9] For reviews, see: a) H.-U. Reissig, R. Zimmer, Chem. Rev. 2003,
103, 1151–1196; b) C. A. Carson, M. A. Kerr, Chem. Soc. Rev. 2009,
38, 3051–3060; for representative examples with cyclopropane di-
This work was generously supported by the Deutsche Forschungsgemein-
schaft. We thank Evonik, Chemetall, and BASF for the donation of
chemicals and Prof. H. Krautscheid and Dr. P. Lçnnecke (University of
Leipzig) for solving the crystal structures.
AHCTUNGTREGeNNUN sters, see: c) C. A. Carson, M. A. Kerr, J. Org. Chem. 2005, 70,
8242–8244; d) Y.-B. Kang, Y. Tang, X.-L. Sun, Org. Biomol. Chem.
2006, 4, 299–301; e) S. D. R. Christie, R. J. Davoile, R. C. F. Jones,
Org. Biomol. Chem. 2006, 4, 2683–2684; f) A. B. Leduc, M. A. Kerr,
Angew. Chem. 2008, 120, 8063–8066; Angew. Chem. Int. Ed. 2008,
47, 7945–7948; g) S. K. Jackson, A. Karadeolian, A. B. Driega,
M. A. Kerr, J. Am. Chem. Soc. 2008, 130, 4196–4201; h) A. T. Par-
sons, A. G. Smith, A. J. Neel, J. S. Johnson, J. Am. Chem. Soc. 2010,
132, 9688–9692; i) S. Xing, W. Pan, C. Liu, J. Ren, Z. Wang, Angew.
Chem. 2010, 122, 3283–3286; Angew. Chem. Int. Ed. 2010, 49, 3215–
3218; for MgI2-catalyzed ring expansion of cyclopropane carboxa-
mides, see: j) P. B. Alper, C. Meyers, A. Lerchner, D. R. Siegel,
E. M. Carreira, Angew. Chem. 1999, 111, 3379–3381; Angew. Chem.
Int. Ed. 1999, 38, 3186–3189; k) A. Lerchner, E. M. Carreira, J. Am.
Chem. Soc. 2002, 124, 14826–14827; l) F. Bertozzi, M. Gustafsson,
R. Olsson, Org. Lett. 2002, 4, 3147–3150; m) M. Lautens, W. Han, J.
Am. Chem. Soc. 2002, 124, 6312–6316; n) C. Meyers, E. M. Carreira,
Angew. Chem. 2003, 115, 718–720; Angew. Chem. Int. Ed. 2003, 42,
694–696; o) M. E. Scott, W. Han, M. Lautens, Org. Lett. 2004, 6,
3309–3312; p) C. Taillier, M. Lautens, Org. Lett. 2007, 9, 591–593.
[10] For related bicyclic N-heterocycles, mainly lactams, see: a) G. Trapa-
ni, M. Franco, A. Latrofa, A. Carotti, S. Cellamare, M. Serra, C. A.
Ghiani, G. Tuligi, G. Biggio, G. Liso, J. Pharm. Pharmacol. 1996, 48,
834–840; b) T. Aicher, B. Balkan, P. A. Bell, L. J. Brand, S. H.
Cheon, R. O. Deems, J. B. Fell, J. Med. Chem. 1998, 41, 4556–4566;
c) O. David, S. Calvet, F. Chau, C. Vanucci-Bacque, M.-C. Fargeau-
Bellassoued, G. Lhommet, J. Org. Chem. 2004, 69, 2888–2891.
[11] a) M. Sickert, C. Schneider, Angew. Chem. 2008, 120, 3687–3690;
Angew. Chem. Int. Ed. 2008, 47, 3631–3634; b) D. S. Giera, M. Sick-
ert, C. Schneider, Org. Lett. 2008, 10, 4259–4262; c) M. Sickert, F.
Abels, M. Lang, J. Sieler, C. Birkemeyer, C. Schneider, Chem. Eur.
J. 2010, 16, 2806–2818; d) F. Abels, C. Schneider, Synthesis 2011,
4050–4058.
Keywords: asymmetric synthesis
heterocycles · Lewis acids · N,O-acetal
· domino reactions ·
[1] For reviews, see: a) R. V. A. Orru, M. de Greef, Synthesis 2003,
1471–1499; b) D. Sunderhaus, S. F. Martin, Chem. Eur. J. 2009, 15,
1300–1308; c) B. B. Tourꢄ, D. G. Hall, Chem. Rev. 2009, 109, 4439–
4486; d) J. Yu, F. Shi, L.-Z. Gong, Acc. Chem. Res. 2011, 44, 1156–
1171; e) E. Ruijter, R. Scheffelaar, R. V. A. Orru, Angew. Chem.
2011, 123, 6358–6371; Angew. Chem. Int. Ed. 2011, 50, 6234–6246;
f) see also a thematic issue: H. M. L. Davies, E. J. Sorensen, Chem.
Soc. Rev. 2009, 38, 2981–2982.
[2] For reviews, see: a) L. F. Tietze, Chem. Rev. 1996, 96, 115–136;
b) L. F. Tietze, A. Modi, Med. Res. Rev. 2000, 20, 304–322; c) L. F.
Tietze, N. Rackelmann, Pure Appl. Chem. 2004, 76, 1967–1983;
d) L. F. Tietze, G. Brasche, K. M. Gericke, Domino Reactions in Or-
ganic Synthesis, Wiley-VCH, Weinheim, 2006; e) K. C. Nicolaou,
D. J. Edmonds, P. G. Bulger, Angew. Chem. 2006, 118, 7292–7344;
Angew. Chem. Int. Ed. 2006, 45, 7134–7186.
[3] For recent reviews, see: a) D. OꢃHagan, Nat. Prod. Rep. 2000, 17,
435–446; b) J. R. Liddell, Nat. Prod. Rep. 2002, 19, 773–781; c) F.-
X. Felpin, J. Lebreton, Eur. J. Org. Chem. 2003, 3693–3712; d) E.
De Clercq, Nat. Rev. Drug Discovery 2006, 5, 1015–1025; e) J. P. Mi-
chael, Nat. Prod. Rep. 2008, 25, 139–165.
[4] For pyrroloindolines, see: a) A. Steven, L. E. Overman, Angew.
Chem. 2007, 119, 5584–5605; Angew. Chem. Int. Ed. 2007, 46, 5488–
5508; b) D. Crich, A. Banerjee, Acc. Chem. Res. 2007, 40, 151–161;
c) J. Kim, M. Movassaghi, Chem. Soc. Rev. 2009, 38, 3035–3050; for
pyrroloisoquinolines, see: d) H. Fan, Peng, J. M. K. Hamann, J.-F.
Hu, Chem. Rev. 2008, 108, 264–287; for pyrrolobenzodiazepines,
4188
www.chemeurj.org
ꢂ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2012, 18, 4185 – 4189

A Three-Component [3+2] Cycloannulation Process
COMMUNICATION
[12] For reviews, see: a) H. Ahlbrecht, U. Beyer, Synthesis 1999, 365–
390; b) V. Nair, S. Vellalath, B. P. Babu, Chem. Soc. Rev. 2008, 37,
2691–2698.
15.5961(3); b=10.9133(2), c=9.2802(2) ꢇ; a=90, b=90, g=908;
V=1579.54(5) ꢇ3; Z=4; 1calcd =1.284 gcmꢀ3; m=0.083 mmꢀ1; MoKa
radiation; l=0.71073 ꢇ; T=130(2) K; 18137 measured and 4824 in-
[13] a) D. A. Nicewicz, J. S. Johnson, J. Am. Chem. Soc. 2005, 127, 6170–
6171; b) D. A. Nicewicz, A. D. Satterfield, D. C. Schmitt, J. S. John-
son, J. Am. Chem. Soc. 2008, 130, 17281–17283; for a g-selective vi-
nylogous Michael addition to nitroalkenes, see: c) G. R. Boyce, J. S.
Johnson, Angew. Chem. 2010, 122, 9114–9117; Angew. Chem. Int.
Ed. 2010, 49, 8930–8933.
[14] a) S. P. Marsden, R. Newton, J. Am. Chem. Soc. 2007, 129, 12600–
12601; b) S. P. Marsden, R. Newton, Synthesis 2005, 3263–3270.
[15] Brønsted acid catalyzed reactions of nucleophile 1 with imines give
mixtures of a- and g-regioisomers.
dependent reflections; qmax =30.508; Rint =0.0301; R1ACTHGUNTREN(NUNG I>2s(I))=
0.0314; wR2 (all data)=0.0624; 284 parameters; D1max/min =0.223/
ꢀ0.172 eꢇꢀ3
; structure determination by direct methods (G. M.
Sheldrick, SHELXS-97, 1998) and by least-squares refinement on
F2o(G. M. Sheldrick, SHELXL-97, 1997). CCDC-862016 contains the
supplementary crystallographic data for this paper. These data can
be obtained free of charge from The Cambridge Crystallographic
Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
[19] For a review, see: X. Liu, L. Lin, X. Feng, Acc. Chem. Res. 2011, 44,
574–587.
[16] The intermediate vinylogous Mannich product was characterized by
HRMS and 1H NMR spectroscopy measurements, see the Support-
ing Information.
[20] See the Supporting Information for ORTEP picture of (1R,3aR)-3k.
Crystal data for (1R,3aR)-3k: C19H18BrNO3; Mr =388.25 gmolꢀ1
;
crystal size: 0.50ꢆ0.40ꢆ0.20 mm3; monoclinic; space group P21; a=
10.7744(9), b=7.2784(5), c=11.774(1) ꢇ; a=90, b=108.23(1), g=
[17] Crystal data for (rac)-3a: C19H19NO3; Mr =309.35 gmolꢀ1; crystal
size: 0.30ꢆ0.30ꢆ0.20 mm3; monoclinic; space group P21/n; a=
11.7951(4), b=7.2664(2), c=17.9472(6) ꢇ; a=90, b=91.571(3), g=
908; V=877.0(1) ꢇ3; Z=2; 1calcd =1.470 gcmꢀ3
; ;
m=2.360 mmꢀ1
MoKa radiation; l=0.71073 ꢇ; T=213(2) K, 15257 measured and
4048 independent reflections, qmax =27.968; int =0.0747; R1-
908; V=1537.64(8) ꢇ3; Z=4; 1calcd =1.336 gcmꢀ3; m=0.090 mmꢀ1
;
R
MoKa radiation; l=0.71073 ꢇ; T=180(2) K; 10190 measured and
3643 independent reflections; qmax =27.898; int =0.0238; R1-
ACHTUNGTREN(NUGN I>2s(I))=0.0265; wR2 (all data)=0.0491; 289 parameters; absolute
R
structure parameter ꢀ0.012(6); D1max/min =0.381/ꢀ0.351 eꢇꢀ3; struc-
(I>2s(I))=0.0354; wR2 (all data)=0.0977; 284 parameters; D1max/
ture determination by direct methods (G. M. Sheldrick, SHELXS-
min =0.272/ꢀ0.178 eꢇꢀ3 structure determination by direct methods
97, 1990) and by least-squares refinement on F2 (G. M. Sheldrick,
,
o
(G. M. Sheldrick, SHELXS-97, 1990) and by least-squares refine-
SHELXL-97, 1997). CCDC-862017 contains the supplementary crys-
tallographic data for this paper. These data can be obtained free of
charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
ment on F2 (G. M. Sheldrick, SHELXL-97, 1997). CCDC-862018
o
contains the supplementary crystallographic data for this paper.
These data can be obtained free of charge from The Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/
cif.
[18] Crystal data for (rac)-6: C20H19NO2; Mr =305.36 gmolꢀ1; crystal size:
0.40ꢆ0.30ꢆ0.20 mm3; orthorhombic; space group Pna21; a=
Received: February 7, 2012
Published online: March 12, 2012
Chem. Eur. J. 2012, 18, 4185 – 4189
ꢂ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
4189