A highly convergent synthesis of tricyclic n-heterocycles coupling an ugi reaction with a tandem Sn2′-heck double cyclization

Article abstract of DOI:10.1021/jo100859y

(Figure presented) A small library of natural product-like compounds has been assembled by coupling an Ugi multicomponent reaction with two postcondensation transformations, carried out in one-pot fashion: a S _N2′ cyclization followed by an intramolecular Heck reaction.

Full text of DOI:10.1021/jo100859y

pubs.acs.org/joc
A Highly Convergent Synthesis of Tricyclic N-Heterocycles Coupling an
Ugi Reaction with a Tandem SN20-Heck Double Cyclization
Renata Riva,* Luca Banfi, Andrea Basso, Valentina Cerulli, Giuseppe Guanti, and
Marcella Pani
Dipartimento di Chimica e Chimica Industriale, Via Docecaneso 31, 16146 Genova, Italy
riva@chimica.unige.it
Received April 30, 2010
A small library of natural product-like compounds has been assembled by coupling an Ugi multi-
component reaction with two postcondensation transformations, carried out in one-pot fashion:
a SN20 cyclization followed by an intramolecular Heck reaction.
Introduction
The process of drug discovery often requires rapid entry to
a broad array of molecular architectures of heterocyclic
nature: to achieve this goal, several approaches have been
proposed. The diversity-oriented synthesis paradigm1 and
the generation of collections of nature-inspired structures2
are two particularly useful approaches to produce libraries
that effectively cover the chemical space of biologically
relevant structures. The latter approach is based on the
awareness that natural products are a source of many new
drugs and that these have been selected by their evolutionary
history for biological activity.3
FIGURE 1. Cephalotaxus alkaloids.
the introduction of up to four diversity points fits parti-
cularly well into the guiding principles of DOS.
Our group has been involved in several projects aimed at
the development of highly convergent syntheses of hetero-
cycles, privileged structures in drug discovery. Our contribu-
tion in this field has been attained mainly by coupling multi-
component reactions, as Ugi or Passerini (U- or P-MCR)
reactions that typically lead to acyclic peptidic or depsipep-
tidic skeletons, with a secondary transformation. This metho-
dology enables generation of various heterocyclic systems.4
The high rate of complexity increase per synthetic step and
An exceptionally relevant group of natural substances is
represented by alkaloids. Within this class, a particularly inter-
esting category are the rare Cephalotaxus alkaloids (Figure 1),
extracted from the evergreen conifer Cephalotaxus harringtonia,
well represented by the parent member cephalotaxin bearing a
pentacyclic skeleton and featuring a unique benzazepine moiety.
Their naturally occurring esters, harringtonine and homo-
harringtonine, are highly effective for the treatment
of acute human leukemia and are currently undergoing
advanced clinical trials. Homorarringtonine is also a potent
in vitro agent against a strain of chloroquine-resistant Plasmo-
dium falciparum, responsible for malaria.5
(1) Schreiber, S. L.; Burke, M. D. Angew. Chem., Int. Ed. 2004, 43, 46–58.
(2) (a) Shang, S.; Tan, D. S. Curr. Opin. Chem. Biol. 2005, 9, 248–258.
(b) Nandy, J. P.; Prakesch, M.; Khadem, S.; Thirupathi Reddy, P.; Sharma,
U.; Arya, P. Chem. Rev. 2009, 109, 1999–2060.
(3) Clardy, J.; Walsh, C. Nature 2004, 432, 829–837.
(4) (a) Banfi, L.; Riva, R.; Basso, A. Synlett 2010, 23–41. (b) Basso, A.;
Banfi, L.; Riva, R. Eur. J. Org. Chem. 2010, 1831–1841. (c) Banfi, L.; Basso,
A.; Riva, R. In Topics in Heterocyclic Chemistry; Springer-Verlag: Berlin/
Heidelberg, 2010; Vol. 23, pp 1-40.
(5) Kantarjian, H. M.; Talpaz, M.; Santini, V.; Murgo, A.; Cheson, B.;
O’Brien, S. M. Cancer 2001, 92, 1591–1605.
5134 J. Org. Chem. 2010, 75, 5134–5143
Published on Web 06/24/2010
DOI: 10.1021/jo100859y
r
2010 American Chemical Society

Riva et al.
JOCArticle
FIGURE 2. Retro-synthetic plan.
We were attracted by the structure of these compounds, since
we foresaw the possibility for a quick access to a simplified ver-
sion of its skeleton. We planned, therefore, to synthesize a
library of original, nature-inspired compounds through the stra-
tegy described in the retro-synthetic plan reported in Figure 2.
In detail, we planned to couple an U-MCR (to access key
intermediate c) with a Pd(0)-mediated SN20 cyclization (yielding
to b), where the secondary amide acts as the nucleophile,6,7
and completing the transformation into a by means of an
intramolecular Heck reaction. Although tandem Ugi/Heck
strategies8 and examples of intramolecular Heck cyclization
followed by a second Pd(0)-catalyzed reaction in a tandem
mode are known,9 the novelty of our protocol stems from the
combination of two palladium-catalyzed secondary trans-
formations in a one-pot fashion. In the chemistry described
herein, the Heck cyclization occurs second, thanks to the
formation of the vinylpyrrolidine moiety. To the best of our
knowledge, this is unprecedented.
This first cyclization was poorly stereoselective, the dia-
stereomeric ratios being in all cases in the range 51:49/60:40
(HPLC). This disappointing stereoselectivity, however, gives
the opportunity to prepare a diverse collection of com-
pounds, as long as the two diastereoisomers can be sepa-
rated, by a single combination of reagents.
Separation of the two diastereomers by chromatography was
not possible at this stage, but it was easily done at the end of
the synthetic sequence. Therefore, the purified diastereomeric
mixtures of 3 were directly submitted to the following Heck
cyclization without accurate spectroscopic characterization. In
3, the restricted rotation around the two amide bonds gives rise
to various rotamers, resulting in very complex 1Hor13C spectra
at room temperature, whereas at 120 °C, broad peaks were
always observed.6,10 The situation was further complicated by
the presence of two inseparable diastereomers. HPLC showed
in all cases an overall purity g95% (sum of diastereoisomers)
and allowed the determination of the diastereomeric ratio.
In principle, the intramolecular Heck reaction might afford
two different constitutional isomers arising from a 7-exo (4) or
a 8-endo (6) attack, but isomerized derivatives such as 5 also
can be reasonably expected (Figure 3). Previous synthetic
approaches in the field of alkaloids11 showed a preference for
7-exo products, but the special substitution pattern of our
compounds made the results not fully predictable.
We first optimized the reaction on compound 3a. At room
temperature, the rate of reaction was very slow, and in some
cases, the reaction did not even start; heating was therefore
required. For our purposes, we found the use of microwave
heating at 120 °C to be particularly convenient. We had to
carefully select the catalyst, the phosphine ligand, the sol-
vent, and most of all, the base (Table 2). Several Pd catalysts
were tested [Pd(OAc)2, Pd(PPh3)2Cl2, Pd(PPh3)4]: all of them
promoted the cyclization, but the latter proved to be the most
effective. In particular, Pd(OAc)2 caused also a partial
dehalogenation of starting 3a, which obviously prevented
the Heck cyclization (entry 2, Table 2).
Results and Discussion
The key substrates for this protocol are represented by
isocyanide 1, bearing an allylic alcohol protected as methyl
carbonate, that acts as the leaving group in the SN20 cycliza-
tion, and by a series of o-halobenzaldehydes containing the
aryl halide moiety needed for the Heck step. The synthesis of
1 and the related MCR reactions have been previously
optimized, although on other substrates.6
Following that protocol, we assembled from the poly-
functionalized isocyanide 1 a series of Ugi products 2 with up
to five points of diversity (four of them designed to remain in
the final tricyclic derivatives) (Scheme 1) in excellent yields.
We then turned our attention to the double post-Ugi cycliza-
tion. Initially, we studied the two postcondensation trans-
formation as separate steps. As far as the SN20 cyclizations
were concerned, they could be performed in excellent yields
to afford pyrrolidines 3 using the previously optimized
Pd(0)-catalyzed conditions (Table 1).6
Addition of the phosphine ligand was required; otherwise, the
yields were unsatisfactory (entry 5, Table 2). A careful selection
of the ligand and of its relative amount (with respect to the cata-
lyst) was also very important: we found an equimolar amount
(relative to Pd) of 1,2-diphenylphosphinoethane (DPPE) to be
the best. Nevertheless, the most crucial parameter to be opti-
mized turned out to be the base. Heck reactions are usually
performed in the presence of triethylamine. Even if the yield was
in one case excellent (92%) (entry 8, Table 2), the results were
poorly reproducible, both in terms of yield and conversion.
(6) Banfi, L.; Basso, A.; Cerulli, V.; Guanti, G.; Riva, R. J. Org. Chem.
2008, 73, 1608–1611.
€
(7) (a) Bulusu, M. A. R. C.; Waldstatten, P.; Tricotet, T.; Rochais, C.;
Steck, A.; Bacher, M. Tetrahedron Lett. 2004, 45, 5833–5836. (b) Berkowitz,
D. B.; Gourhari Maiti, G. Org. Lett. 2004, 6, 2661–2664.
(8) (a) Gracias, V.; Moore, J. D.; Djuric, S. W. Tetrahedron Lett. 2004, 45,
417–420. (b) Xiang, Z.; Luo, T.; Lu, K.; Cui, J.; Shi, X.; Fathi, R.; Chen, J.;
Yang, Z. Org. Lett. 2004, 6, 3155–3158. (c) Umkehrer, M.; Kalinski, C.;
Kolb, J.; Burdack, C. Tetrahedron Lett. 2006, 47, 2391–2393. (d) Kalinski,
C.; Umkehrer, M.; Schmidt, J.; Ross, G.; Kolb, J.; Burdack, C.; Hiller, W.;
Hoffmann, S. D. Tetrahedron Lett. 2006, 47, 4683–4686. (e) Ribelin, T. P.;
Judd, A. S.; Akritopoulou-Zanze, I.; Henry, R. F.; Cross, J. L.; Whittern,
D. N.; Djuric, S. W. Org. Lett. 2007, 9, 5119–5122. (f) Dai, W.-M.; Shi, J. Y.;
Wu, J. L. Synlett 2008, 2716–2720.
(10) Banfi, L.; Basso, A.; Guanti, G.; Merlo, S.; Repetto, C.; Riva, R.
Tetrahedron 2008, 64, 1114–1134.
(9) (a) Ruck, R. T.; Huffman, M. A.; Kim, M. K.; Shevlin, M.; Kandur,
W. V.; Davies, I. W. Angew. Chem., Int. Ed. 2008, 47, 4711–4714. (b) Zegar,
S.; Tokar, C.; Enache, L. A.; Rajagopol, V.; Zeller, W.; O’Connell, M.;
Singh, J.; Muellner, F. W.; Zembower, D. E. Org. Process Res. Dev. 2007, 11,
747–753.
(11) (a) Ikeda, M.; Hirose, K.; El Bialy, S. A. A.; Sato, T.; Yakura, T.;
Bayomi, S. M. M. Chem. Pharm. Bull. 1998, 46, 1084–1089. (b) Tietze, L. F.;
Burkhardt, O.; Henrich, M. Liebigs Ann. 1997, 1407–1413. (c) Tietze, L. F.;
€
Schirok, H.; Wohrmann, M.; Schrader, K. Eur. J. Org. Chem. 2000, 2433–
2444.
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SCHEME 1. Ugi Reaction Followed by a Two-Step SN20-Heck Sequence
TABLE 1. Ugi Reaction Followed by SN20 Reactiona
reaction conditions, all of other derivatives were smoothly
converted into the tricyclic derivatives.
yieldb (%)
Ugic SN20
Br 2a: 96 3a: 98
entry
R1
R2
R3
R4
X
1
2
3
4
5
Et
Et
Et
Ph
Ph
Bn
Bn
nBu
iBu
iBu
H
H
H
F
H
H
H
H
H
I
2b: 94 3b: 95
Br 2c: 85 3c: 99
Br 2d: 78d 3d: 96
H
I
Br 2f: 84
2e: 77
3e: 90
3f: 94
6
CH2OMe Bn
OCH2O
7
8
9
10
CH2OMe CH2(2-furyl)
CH2OMe CH2(2-furyl)
CH2OMe Ph
H
F
H
F
H
H
H
H
I
2g: 86 3g: 100
Br 2h: 81 3h: 95
2i: 89 3i: 95
Br 2j: 72d 3j: 95
I
(CH2)2-
NHCbz
CH2(2-furyl)
aThe experimental conditions depicted in Scheme 1 have been followed.
bAfter chromatography. cIn the U-MCR either all the reagents have been
mixed together at the same time (entries 1-3) or the imine has been
preformed before addition of 1 and R1-CO2H (entries 4-10). dIn this case,
a variable amount of the Passerini product has also been isolated.
FIGURE 3. Possible intramolecular Heck products (racemic form).
In all cases, the major products were the diastereomeric cis
and trans 7-exo derivatives 4. In addition to them, we were,
however, able to detect and isolate (sometimes as inseparable
mixtures) small amounts of other Heck products, including
derivatives arising from intermolecular reactions (see Table 3).
In some cases, we identified, among them, 8-endo derivatives 6.
For example, starting from the diastereomeric mixture of 3d
(entry 4, Table 3), cis-4d was obtained only in traces, and a
single diastereomer of 6d (presumably the cis one) was isolated
instead. On the contrary, the reaction of the other diastereomer,
leading to trans-4d proceeded efficiently as usual. In addition, in
the reaction mixture derived from compound 3h (entry 8,
Table 3), we were also able to isolate the isomerized adduct
5h as an inseparable mixture with cis-4h.
The nature of the halogen atom influences the reaction
outcome, with the cyclization running faster and cleaner
when iodo derivatives were employed (compare entries 1 and
2 of Table 3, leading to the same tricyclic derivative).
The relative configuration of cis- and trans-4a was un-
ambiguously established as follows. First, a series of NOE
experiments displayed the interactions between the protons
shown in Figure 4. The most diagnostic result is the very
strong NOE effect between the H bonded to the two stereo-
genic centers observed in cis-4a (higher Rf in TLC), while this
NOE was completely absent in trans-4a (lower Rf in TLC).
trans-4a displayed, on the other side, a strong NOE between
the benzylic H and the aromatic H in the peri position.
Changing the base to cesium carbonate led to a reproducible
enough reaction, and moreover, it was always possible to drive
the reactions to completion (entry 1, Table 3). Initially, we
performed the reaction in acetonitrile, one of the most widely
used solvents for the Heck reactions, but after several experi-
ments, we found that DMF was better suited.
The two diastereomers of 4a could be easily separated at
this stage by chromatography and were fully characterized
(see below). Although the diastereomeric ratio was similar to
the one determined on 3a (55:45 vs 60:40), we wanted to verify
the correspondence of the major diastereomers. Separation at the
level of 3a was definitely difficult, but we succeeded in obtaining
small amounts (∼10 mg) of the separated diastereomers and to
submit them independently to the Heck reaction. Surprisingly,
the major isomer afforded cis-4a in only 48% yield, whereas
the minor isomer gave trans-4a in 93% yield (cis and trans are
referred to the relative position of the hydrogens bonded to the
two stereogenic carbons). Therefore, the Heck cyclization is
highly dependent on the relative configuration of the starting
haloarene, and the moderate overall yield (69%) is due only to
the poorer contribution of the cis adduct 4a. As can be seen from
Table 3, this behavior was found to be pretty general, and trans-4
was in most cases isolated as the major diastereomer.
The scope of the methodology was also transferred to the
other pyrrolidines. With the exception of compounds 3g and
3j, which underwent extensive decomposition under the
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JOCArticle
TABLE 2. Optimization of the Heck Cyclization Conditions for Preparation of 4a
phosphine/
catalystb
temp, microwave
heatingd
entrya
catalyst (%)
phosphine
PPh3
PPh3
base (equiv)c
solvent
comments, yielde, f
sluggish
not complete and partial
dehalogenation, up to 50%
not complete, 35%
up to 70%
1
2
Pd(OAc)2 (20%)
Pd(OAc)2 (20%)
3:1
3:1
Et3N (10)
Et3N (10)
MeCN
MeCN
60 °C, no MW
150 °C, MW
3
4
5
6
7
8
Pd(PPh3)2Cl2 (10%)
Pd(PPh3)2Cl2 (10%)
Pd(PPh3)4 (10%)
Pd(PPh3)4 (10%)
Pd(PPh3)4 (10%)
Pd(PPh3)4 (7-10%)
PPh3
PPh3
no phosphine
DPPE
DPPE
1:1
1:1
Et3N (2)
Et3N (2)
Et3N (2)
Et3N (2)
Et3N (2)
Et3N (2-3)
MeCN
DMF
DMF
DMF
DMF
DMF
c
120 °C, MW
120 °C, MW
120 °C, MW
120 °C, MW
100 °C, no MW
120 °C, MW
up to 30%
2:1
1:1
1:1
traces of cyclization products
no reaction
up to 92%, not reproducible
DPPE
aCyclization attempts have been performed on substrate 3a (X = Br). bMolar ratio. Equivalents with respect to the substrate. dAll reactions
performed under microwave heating have been done in a closed vessel. eIn most cases, the reaction was performed more than once, and for this reason,
an average yield is reported. fYield includs all Heck products.
TABLE 3. Heck Cyclization under Optimized Conditionsa
yield (%)b
[4 (cis/trans ratio)]
yield (%)c
(side products)
entry
substrate
X
1
2
3
4
5
6
7
8
9
10
3a
3b
3c
3d
3e
3f
3g
3h
3i
Br
I
Br
Br
I
Br
I
Br
I
4a: 69 (45:55)
4a: 81 (54:46)
4c: 68 (37:63)
4d: 26 (trace:∼100)
4e: 61 (30:70)
4f: 63 (48:52)
4g: -
15
13
14
20 (6d)
35
15
4h: 41 (39d:61)
4i: 65 (37:63)
4j: -
26
20
3j
Br
aThe experimental conditions depicted in Scheme 1 have been fol-
lowed. bSum of the isolated yields of separated cis and trans diastereo-
mers; the cis/trans ratio was determined by weight. See text. dThis is
actually an unseparable 61:39 mixture of cis-4h and 5h.
c
This result is in agreement with the proposed relative con-
figuration because, according to the rigid conformation of
these compounds, this benzylic hydrogen occupies an equa-
torial position in trans-4a, whereas it is axial in cis-4a.
Finally, a strong effect, although not diagnostic for the
attribution of relative configuration, was found between
the exo methylene H directed toward the aromatic ring and
the aromatic H in the homoallylic position.
FIGURE 5. X-ray structure of trans-4a.
the peri hydrogen, and this may explain the more difficult
formation of this stereoisomer.
Another important feature shown by crystallography is
the position of the exo methylene: in the crystal structure of
trans-4a it is not coplanar with the aromatic ring, thus
preventing an extended conjugation.
The relative configuration of the other compounds 4 was
assigned thanks to strong spectroscopic and chromato-
graphic analogies.
FIGURE 4. Significant NOE effects in cis- and trans-4a.
These results, obtained in solution, are also in perfect
agreement with the solid-state structure, determined through
single-crystal X-ray analysis on trans-4a. As can be seen in
Figure 5,12 the benzylic H occupies an equatorial position,
with the C-H bond being nearly coplanar with the aromatic
ring, whereas the bulky tertiary amide is nearly orthogonal to
the same plane. Accordingly, in cis-4a, the tertiary amide is
expected to be equatorial and the hydrogen axial (as demon-
strated by the absence of a NOE with the peri hydrogen). The
nearly coplanar position of the bulky tertiary amide is
expected to determine an unfavorable steric interaction with
The two stereoisomers of 4 were always well separated in
TLC, and the cis diastereomer was always the one with higher
Rf. Proton spectra showed interesting analogies: the benzylic
proton alway resonates downfield in the cis stereoisomer
(δ 5.74-6.47) with respect to the trans one (δ 4.75-5.50) with
a difference in chemical shift up to 1.69 ppm (average Δδ 1.23).
An opposite trend is displayed in the 13C NMR spectra, where
the corresponding carbon of the cis stereoisomer is always
upfield (δ 57.8-65.3) with respect to the trans (δ 65.9-69.1)
with a difference in chemical shift up to 10.3 ppm (average Δδ
6.6).13 A less remarkable but recurrent difference is shown by
(12) Figure 5 shows a ball and stick model of trans-4a obtained from the
ORTEP included in the Supporting Information.
(13) Additional details are reported in the Supporting Information.
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JOCArticle
TABLE 4. Tandem SN20-Heck Sequence Converting 2 into 4
employing a diversity oriented approach with the generation
of high complexity in just two synthetic steps, resulting in a
new methodology for building nature-inspired libraries.
yield (%)
entry
substratea
4 (cis/trans ratio)b
side products
1
2
3
2a
2b
2c
4a: 59 (54:46)
4a: 91 (53:47)
4c: 58 (43:57)
33
8
23
Experimental Section
General Experimental Details. Petroleum ether (40-60 °C)
is abbreviated as PE. In extractive workup, aqueous solu-
tions were always reextracted three times with the appropriate
organic solvent. Organic extracts were washed with brine, dried
over Na2SO4, and filtered before evaporation of the solvent
under reduced pressure. All reactions employing dry solvents
were carried out under a nitrogen (Ugi reactions) or ultrapure
argon (SN20 and Heck reactions) atmosphere.
aConditions: (1) Pd(PPh3)4 (10%), DPPE (10%), DMF, 120 °C, MW,
1 h; (2) Cs2CO3 (2 equiv), 120 °C, MW, 1 h. bSee note b, Table 3.
the allylic R proton to the pyrrolidine nitrogen: it always
resonates downfield (δ 4.48-4.79), as a triplet, in the cis stereo-
isomer, whereas in the trans one it appears either as a broad
triplet, a broad doublet of doublet, or a symmetric multiplet
(δ 4.26-4.55), with a difference in chemical shift up to 0.51 ppm
(average Δδ 0.24). The differences in chemical shift of the
corresponding carbons, on the contrary, are much less pro-
nounced, with the cis giving typically higher δ values. On the
contrary, no correlation between the chemical shifts and the
configuration for the exo methylene hydrogens and carbons was
found. Although the methylene carbon usually resonates upfield
in the cis stereoisomer, the average difference of only 1.25 ppm
does not allow a clear correlation.
Having demonstrated the feasibility of the protocol, the
following step was to find conditions able to convert the Ugi
adducts 2 into 4 in a one-pot manner, without the need of
isolating the intermediate pyrrolidines 3. For this purpose, we
had to find conditions consistent with the two palladium(0)-
catalyzed processes that have in part different requirements.
Similar conditions were therefore first investigated inde-
pendently on both reactions. The first cyclization, which,
according to the previously reported procedure, can be
performed by conventional heating at 60 °C, could also be
successfully performed under microwave heating at 120 °C
by halving the reaction time. Moreover, acetonitrile, which
was previously used for the SN20 reaction, could be success-
fully substituted by DMF, the best solvent for the subsequent
Heck step. Finally, the same catalyst and ligand were com-
patible with both reactions. However, it was impossible to
perform the whole sequence as a domino process because the
presence of a stoichiometric amount of base, necessary for
the Heck reaction, turned out to be poorly compatible with
the SN20 step. For these reasons, we preferred a one-pot
sequence in which the base was added in the same vessel after
consumption of the Ugi product. Then, additional warming
under microwave heating allowed the complete conversion
into the desired tricyclic derivatives.
General Procedure for the Ugi Reactions. Without preforma-
tion of the imine (entries 1-3, Table 1): A solution of isocyanide
1, an ∼95:5 mixture of E and Z diastereomers prepared follow-
ing our previously reported procedure6 (0.5-2 mmol), in dry
CF3CH2OH/EtOH 1:1 (∼0.4 M solution) was treated with
˚
activated 4 A powdered molecular sieves (50 mg/mmol of
aldehyde). Aldehyde (1.1 equiv), amine (1.15 equiv), and car-
boxylic acid (1.2 equiv) were then added. The reaction was
stirred at 45 °C until complete (8-16 h).
Preformation of the imine (entries 4-10, Table 1): A solution
of aldehyde (1.2 mmol) in dry CF3CH2OH/EtOH 1:1 (∼0.4 M
˚
solution) was treated with activated 4 A powdered molecular
sieves (50 mg/mmol of aldehyde) and stirred at 45 °C for 6 h.
Then isocyanide 1 (1.0 mmol) and acid (1.2 mmol) were added,
and the mixture was stirred again at 45 °C until completion of
the reaction (4-24 h).
In both procedures, after filtration of the sieves, the mixture
was diluted with EtOAc and extracted. Then the organic layer
was washed with saturated aqueous NaHCO3 solution, dried,
and concentrated in vacuo. The crude was purified by chromato-
graphy.
Notice that proton spectra at room temperature are a mixture
of two highly prevailing rotamers (with the exception of com-
pound 2i), and for this reason, they have been recorded at higher
temperature (80, 90, or 120 °C). However, in all cases where the
ratio of the rotamers at rt is readily accessible by integration of
suitable signals, the value is reported in the appropriate section.
In the 13C spectra, where the signal of both rotamers can be
identified, “M” indicates the major rotamer and “m” the minor
one.
2-(N-Benzylpropionamido)-2-(2-bromophenyl)-N-(E)-6-(((me-
thoxycarbonyl)oxy)hex-4-en-1-yl)acetamide (2a). Chromato-
graphy with PE/EtOAc 6:4 (þ 1% EtOH) f 1:1 (þ 1% EtOH).
Yield: 96%. State: colorless oil. Rf = 0.73 (PE/EtOAc 2:8). IR:
ν
max 3428, 2985, 1742, 1652, 1440, 1266, 971, 928. HR-MS: calcd
for C26H31BrN2O5 530.1416, found 530.1412, -0.8 ppm. GC-
MS: unsuitable for this analysis. 1H NMR (DMSO-d6, temp=
90 °C): δ 1.04 (3H, t, J=7.2 Hz), 1.48 (2H, quintuplet, J=7.1
Hz), 2.04 (2H, br q, J=7.1 Hz), 2.37 (2H, center of m), 3.09 (2H,
center of m), 3.72 (3H, s), 4.54 (2H, dd, J=6.0, 1.2 Hz), 4.49 and
4.77 (2H, AB system, J=16.5 Hz), 5.52-5.83 (2H, m), 6.10 (1H,
br s), 6.90-7.38 (8H, m), 7.43 (1H, d, J=7.8 Hz), 7.97 [1H, br s;
at rt: 2 signals in 61:39 ratio at 8.26 (br t, J=5.2 Hz) and 8.43 (br
t, J=5.0 Hz), respectively]. 13C NMR (DMSO-d6): δ 9.2 (m) and
9.3 (M) (CH3), 25.8 (m) and 26.3 (M) (CH2), 27.7 (m) and 27.8
(M) (CH2), 28.9 (CH2), 38.1 (CH2), 47.5 (m) and 48.5 (M) (CH2),
54.5 (CH3), 61.0 (M) and 63.1 (m) (CH), 67.8 (CH2), 123.8 (M)
and 124.0 (m) (CH), 125.7, 126.3, 126.9, 127.1, 127.5, 127.8,
129.7, 130.0, 130.1, 130.5, 132.6 (9C, CH; 1C, C), 135.3 (m) and
135.9 (M) (C), 135.5 (m) and 135.6 (M) (CH), 138.0 (M) and
138.4 (m), 155.0 (C), 168.3 (m) and 169.0 (M) (C), 173.7 (m) and
174.2 (M) (C).
The results reported in Table 4 show that the one-pot
methodology is indeed comparable or even superior to the
two-step sequence. In particular, best results were obtained
starting from the iodo derivative 2b (entry 2, Table 4).
Interestingly, this time the cis/trans ratios were slightly
different, compared to the two-step protocol, affording a
nearly equimolar mixture of trans and cis isomers.
Conclusions
In conclusion, we prepared a small library of bifunctional-
ized Ugi derivatives that have been submitted to a high-
yielding two-step secondary transformation mediated by
Pd(0). The success in performing the organometallic trans-
formation in a one-pot fashion opens the way to the pre-
paration of highly functionalized polycyclic compounds
2-(N-Benzylpropionamido)-2-(2-iodophenyl)-N-(E)-6-(((methoxy-
carbonyl)oxy)hex-4-en-1-yl)acetamide (2b). Chromatography
5138 J. Org. Chem. Vol. 75, No. 15, 2010

Riva et al.
JOCArticle
128.5 (CH), 134.0 (d, CH, JC-F = 8.1 Hz), 134.9 (CH), 136.7
with PE/EtOAc 6:4 (þ 1% EtOH). Yield: 94%. State: thick
yellow oil. Rf = 0.40 (PE/EtOAc 1:1 þ 1% EtOH). IR: νmax
3433, 2993, 1744, 1699, 1441, 1254, 972, 932. HR-MS: calcd for
C26H31IN2O5 578.1278, found 578.1270, -1.4 ppm. GC-MS:
unsuitable for this analysis. 1H NMR (DMSO-d6, temp = 120 °C):
δ 1.06 (3H, t, J=7.4 Hz), 1.51 (2H, quintuplet, J=7.2 Hz),
2.02 (2H, br q, J=6.7 Hz), 2.28-2.47 (2H, m), 2.99-3.18 (2H,
m), 3.73 (3H, s), 4.46 and 4.72 (2H, AB system, J=17.0 Hz),
4.55 (2H, d, J=6.6 Hz), 5.53-5.84 (2H, m), 5.90 (1H, br s),
6.93-7.20 (6H, m), 7.31-7.37 (2H, m), 7.72 (1H, d, J=7.8 Hz),
7.71 [1H, br s; at rt: 2 signals in 57:43 ratio at 8.22 (br t, J=5.4
Hz) and 8.44 (br t, J=5.2 Hz), respectively]. 13C NMR (DMSO-
d6): δ 9.2 (m) and 9.4 (M) (CH3), 26.0 (m) and 26.4 (M) (CH2),
27.8 (m) and 27.9 (M) (CH2), 28.9 (CH2), 38.2 (CH2), 47.6 (m)
and 48.5 (M) (CH2), 54.5 (CH3), 65.6 (M) and 67.3 (m) (CH),
67.8 (CH2), 103.5 (m), 103.7 (M) (C), 123.8 (M) and 123.9 (m)
(CH), 125.8, 126.0, 126.3, 127.1, 127.3, 127.7, 128.1, 128.3,
129.7, 129.80, 129.83, 130.0 (8C, CH), 135.5 (m) and 135.7
(M) (CH), 138.1 (M) and 138.4 (m) (C), 138.3 (m) and 139.0
(M) (C), 139.4 (CH), 155.0 (C), 168.6 (m) and 169.2 (M) (C),
173.8 (m) and 174.2 (M) (C).
(C), 137.7 (d, C, JC-F = 7.4 Hz), 154.4 (C), 160.7 (d, C, JC-F
244.1 Hz), 167.7 (C), 171.5 (C).
=
2-(2-Iodophenyl)-2-(N-isobutylbenzamido)-N-(E)-6-(((methoxy-
carbonyl)oxy)hex-4-en-1-yl)acetamide (2e). Chromatography
with PE/EtOAc 65:35 f 6:4. Yield: 77%. State: thick pale yellow
oil. Rf = 0.55 (PE/EtOAc 1:1). IR: νmax 2999, 1738, 1699, 1428,
1247, 1191, 971, 925. HR-MS: calcd for C27H33IN2O5 592.1434,
found 592.1422, -2.1 ppm. GC-MS: unsuitable for this analysis.
1H NMR (DMSO-d6, temp = 120 °C): δ 0.54 (3H, t, J = 6.6 Hz),
0.59 (3H, t, J=6.9Hz), 1.39(1H, centerofm),1.54(2H, quintuplet,
J=7.2 Hz), 2.03 (2H, br q, J=7.2 Hz), 3.04 and 3.15 (2H, AB part
of an ABX system, JAB = 14.4 Hz, JAX = 6.6 Hz, JBX = 7.2 Hz),
3.10-3.17 (2H, m), 3.73 (3H, s), 4.55 (2H, dd, J = 6.3, 1.2 Hz),
5.54-5.86 (2H, m), 5.62 (1H, br s) 7.10 (1H, ddd, J = 8.1, 5.7, 3.6
Hz), 7.39-7.46 (7H, m), 7.55 (1H, br s), 7.94 (1H, d, J = 7.8 Hz).
13C NMR (DMSO-d6, temp = 80 °C): δ 19.6 (CH3), 19.8 (CH3),
27.1 (CH), 27.6 (CH2), 28.5 (CH2), 38.0 (CH2), 52.8 (CH2), 54.0
(CH3), 67.3 (CH2), 68.1 (CH), 102.9 (C), 123.5 (CH), 126.1 (2C,
CH), 127.5 (2C, CH), 127.7 (CH), 128.3 (CH), 129.6 (CH), 130.2
(CH), 135.0 (CH), 137.0 (C), 138.2 (C), 139.2 (CH), 154.5 (C),
168.8 (C), 171.4 (C).
2-(2-Bromophenyl)-2-(N-butylpropionamido)-N-(E)-6-(((methoxy-
carbonyl)oxy)hex-4-en-1-yl)acetamide (2c). Chromatography
with PE/EtOAc 6:4 þ 1% EtOH. Yield: 85%. State: thick
yellow oil. Rf = 0.41 (PE/EtOAc 1:1 þ 1% EtOH). IR: νmax
3433, 3002, 1741, 1668, 1635, 1435, 1265, 971, 933. HR-MS:
calcd for C23H33BrN2O5 495.1495 (Mþ - 1), found 495.1489,
-1.1 ppm. GC-MS: unsuitable for this analysis. 1H NMR
(DMSO-d6, temp=90 °C): δ 0.64 (3H, t, J=7.2 Hz), 0.74-0.86
(1H, m), 0.97 (2H, hexuplet, J=7.1 Hz), 1.07 (3H, t, J=7.4 Hz),
1.27-1.41 (1H, m), 1.54 (2H, quintuplet, J=7.1 Hz), 2.04 (2H,
br q, J=7.0 Hz), 2.27-2.47 (2H, m), 3.09-3.21 (4H, m), 3.72
(3H, s), 4.54 (2H, dd, J=6.3, 1.2 Hz), 5.53-5.86 (2H, m), 5.96
(1H, br s), 7.27-7.44 (3H, m), 7.65 (1H, dd, J=7.8, 0.9 Hz), 7.91
[1H, br s; at rt: 2 signals in 69:31 ratio at 8.18 (br t, J=5.4 Hz)
and 8.43 (br t, J=5.2 Hz), respectively]. 13C NMR (DMSO-d6):
δ 9.2 (m) and 9.6 (M) (CH3), 13.3 (m) and 13.4 (M) (CH3), 19.4
(M) and 19.6 (m) (CH2), 25.6 (M) and 25.9 (m) (CH2), 27.9 (m)
and 28.0 (M) (CH2), 28.9 (CH2), 29.7 (m) and 31.1 (M) (CH2),
38.1 (CH2), 44.4 (m) and 45.1 (M) (CH2), 54.5 (CH3), 60.9 (M)
and 63.0 (m) (CH), 67.76 (m) and 67.80 (M) (CH2), 123.9 (M)
and 124.0 (m) (CH), 125.7 (M) and 126.0 (m) (C), 127.7 (M) and
127.9 (m) (CH), 130.0 (M), 130.27 (m), 130.33 (m), 130.8 (M)
(2C, CH), 132.7 (M) and 132.9 (m) (CH), 135.5 (M) and 135.6
(m) (C), 135.7 (M) and 136.2 (m) (CH), 155.0 (C), 168.5 (m) and
169.1 (M) (C), 172.6 (m) and 173.0 (M) (C).
2-(2-Bromo-4-fluorophenyl)-2-(N-isobutylbenzamido)-N-(E)-
6-(((methoxycarbonyl)oxy)hex-4-en-1-yl)acetamide (2d). Chro-
matography with PE/EtOAc 6:4 þ 1% EtOH. Yield: 78%.
State: thick pale yellow oil. Rf=0.57 (PE/EtOAc 1:1). For the
preparation of compound 2d, it was very important to preform
the imine before addition of 1 and the acid. Otherwise, a consi-
derable amount (up to 20%) of Passerini adduct (the benzoate
with O instead of N-i-Bu) was obtained. IR: νmax 3003, 1743,
1669, 1622, 1442, 1193, 971, 928. HR-MS: calcd for C27H32Br-
FN2O5 563.1540 (Mþ þ 1), found 563.1557, -3.0 ppm. GC-
MS: unsuitable for this analysis. 1H NMR (DMSO-d6, temp=
90 °C): δ 0.56 (3H, t, J = 6.6 Hz), 0.63 (3H, t, J = 6.6 Hz), 1.40
(1H, center of m), 1.54 (2H, quintuplet, J = 7.2 Hz), 2.03 (2H, br
q, J = 7.0 Hz), 3.11-3.18 (4H, m), 3.72 (3H, s), 4.55 (2H, dd,
J=6.0, 0.9 Hz), 5.53-5.86 (2H, m), 5.68 (1H, br s; at rt: 2 sing-
lets in 55:45 ratio at 5.26 and 5.92, respectively), 7.16-7.24 (2H,
2-(N-Benzylmethoxyacetamido)-2-(5-bromobenzo[d][1,3]dio-
xol-6-yl)-N-(E)-6-(((methoxycarbonyl)oxy)hex-4-en-1-yl)aceta-
mide (2f). Chromatography with PE/EtOAc 1:1 þ 1% EtOH.
Yield: 84%. State: thick pale yellow oil. Rf = 0.57 (CH2Cl2/
EtOAc 2:8). IR: νmax 3008, 2891, 1739, 1663, 1471, 1247, 1121,
1035, 969, 928. HR-MS: calcd for C27H31BrN2O8 590.1264,
found 590.1251, -2.2 ppm. GC-MS: unsuitable for this anal-
ysis. 1H NMR (DMSO-d6, temp=120 °C): δ 1.52 (2H, quintu-
plet, J=7.1 Hz), 2.03 (2H, br q, J=7.2 Hz), 3.09 (2H, center of
m), 3.32 (3H, s), 3.73 (3H, s), 4.13 (2H, s), 4.45 and 4.77 (2H, AB
system, J = 17.0 Hz), 4.55 (2H, d, J = 6.0 Hz), 5.53-5.85 (2H,
m), 5.89 (1H, br s), 5.98 (1H, s), 6.01 (1H, s), 6.87 (1H, s), 6.91
(1H, s), 7.04-7.17 (5H, m), 7.72 (1H, br s). 13C NMR (DMSO-
d6, temp=80 °C): δ 27.6 (CH2), 28.4 (CH2), 38.0 (CH2), 47.5
(CH2), 54.0 (CH3), 58.0 (CH3), 61.5 (CH), 67.3 (CH2), 70.4
(CH2), 101.6 (CH2), 109.5 (CH), 111.9 (CH), 116.4 (C), 123.6
(CH), 125.7, 126.0, 127.0, (5C, CH), 127.6 (CH), 135.0 (C), 137.5
(C), 146.8 (C), 147.6 (C), 154.5 (C), 168.1 (C), 169.4 (C).
2-(N-((Furan-2-yl)methyl))methoxyacetamido)-2-(2-iodophe-
nyl)-N-(E)-6-(((methoxycarbonyl)oxy)hex-4-en-1-yl)acetamide
(2g). Chromatography with PE/EtOAc 3:7 f 25:75. Yield: 86%.
State: yellow gum. Rf =0.39 (PE/EtOAc 2:8). IR: νmax 3425,
2967, 1743, 1664, 1435, 1265, 1196, 1122, 1010, 970, 934.
HR-MS: calcd for C24H29IN2O7 584.1019, found 584.1010,
-1.5 ppm. GC-MS: unsuitable for this analysis. 1H NMR
(DMSO-d6, temp = 80 °C): δ 1.52 (2H, quintuplet, J = 7.1 Hz),
2.03 (2H, br q, J=7.4 Hz), 3.12 (2H, center of m), 3.35 (3H, s),
3.72 (3H, s), 4.25 and 4.34 (2H, AB system, J = 14.8 Hz),
4.54 (2H, dd, J=6.3, 1.2 Hz), 4.35 and 4.60 (2H, AB system,
J=17.1 Hz), 5.53-5.86 (3H, m), 5.70 (1H, br s), 6.14 (1H, dd,
J=3.0, 1.8 Hz), 7.04 (1H, dt, J=7.5, 1.8 Hz), 7.30-7.33 (2H, m),
7.41 (1H, dt, J=7.5, 1.2 Hz), 7.72 (1H, dd, J=8.1, 1.2 Hz), 7.96
[1H, br s; at rt: two signals in 73:27 ratio at 8.24 (br t, J=5.2 Hz)
and 8.35 (br s), respectively]. 13C NMR (DMSO-d6, temp =
80 °C): δ 27.6 (CH2), 28.4 (CH2), 37.9 (CH2), 40.5 (CH2), 54.2
(CH3), 58.0 (CH3), 65.5 (CH), 67.3 (CH2), 70.1 (CH2), 102.6 (C),
106.4 (CH), 109.5 (CH), 123.6 (CH), 127.6 (CH), 129.4 (CH),
129.8 (CH), 135.0 (CH), 137.8 (CH), 139.1 (CH), 141.1 (C),
150.6 (C), 154.5 (C), 168.3 (C), 169.1 (C).
2-(2-Bromo-4-fluorophenyl)-2-(N-((furan-2-yl)methyl))methoxy-
acetamido)-N-(E)-6-(((methoxycarbonyl)oxy)hex-4-en-1-yl)acet-
amide (2h). Chromatography with PE/EtOAc 1:1 (þ 1% EtOH) f
3:7 (þ 1% EtOH). Yield: 81%. State: yellow solid. Mp: 59.6-
60.2 °C (PE/EtOAc). Rf = 0.26 (PE/EtOAc 1:1 þ 1% EtOH).
IR: νmax 3430, 2995, 1742, 1667, 1442, 1267, 971, 924. HR-MS:
calcd for C24H28BrFN2O7 554.1064, found 554.1071, þ1.3 ppm.
m), 7.36-7.45 (5H, m), 7.71 (1H, dd, JH-H =8.7 Hz, JH-F
=
5.4 Hz), 7.89 (1H, br s). 13C NMR (DMSO-d6, temp = 90 °C): δ
19.4 (CH3), 19.6 (CH3), 27.0 (CH), 27.5 (CH2), 28.4 (CH2), 38.0
(CH2), 53.1 (CH2), 53.9 (CH3), 64.1 (CH), 67.2 (CH2), 116.7 (d,
CH, JC-F = 22.4 Hz), 117.3 (d, CH, JC-F = 24.1 Hz), 119.7 (d,
C, JC-F = 3.2 Hz), 123.6 (CH), 125.9 (2C, CH), 127.6 (2C, CH),
J. Org. Chem. Vol. 75, No. 15, 2010 5139

Riva et al.
JOCArticle
GC-MS: unsuitable for this analysis. 1H NMR (DMSO-d6,
temp=90 °C): δ 1.52 (2H, quintuplet, J=7.1 Hz), 2.04 (2H,
br q, J=7.2 Hz), 3.00-3.19 (2H, m), 3.34 (3H, s), 3.72 (3H, s),
4.26 and 4.29 (2H, AB system, J = 14.7 Hz), 4.49 and 4.67 (2H,
AB system, J=17.1 Hz), 4.54 (2H, dd, J=7.2, 1.2 Hz), 5.53-
5.86 (3H, m), 5.93 (1H, br s), 6.18 (1H, dd, J = 3.3, 1.8 Hz),
7.06-7.31 (3H, m), 7.49-7.55 (1H, m), 8.01 (1H, br s). 13C
NMR (DMSO-d6): δ 27.9 (M) and 28.5 (m) (CH2), 28.9 (M)
(CH2), 38.3 (M) and 38.4 (m) (CH2), 40.6 (m) and 41.2 (M)
(CH2), 54.6 (M) and 54.9 (m) (CH3), 58.4 (CH3), 60.5 (M) and
62.1 (m) (CH), 67.8 (CH2), 69.8 (M) and 71.3 (m) (CH2), 106.8
(CH), 110.2 (CH), 117.0 (d, CH, JC-F = 22.6 Hz, only M), 117.4
(d, CH, JC-F=24.2 Hz, only M), 120.2 (d, C, JC-F=2.9 Hz),
123.6 (m) and 124.0 (M) (CH), 134.1 (d, CH, JC-F=8.2 Hz, only
M), 135.6 (CH), 137.6 (d, C, JC-F=7.4 Hz), 141.1 (m) and 142.2
(M) (CH), 150.5 (M) and 151.3 (m) (C), 155.0 (M) and 155.1 (m)
(C), 161.2 (d, C, JC-F=243.2 Hz), 168.1 (M), 169.3 (m), 169.7
(M) and 170.4 (m) (2C).
considerably slower (2-4 h). For the workup, the crude was
filtered over a Celite pad, and the resulting solution was diluted
with water and extracted with EtOAc. After drying and solvent
removal, the crude was purified by chromatography to give 3 as
a diastereomeric mixture. Pyrrolidines 3 were directly submitted
to the following Heck cyclization.
N-Benzyl-N-(1-(2-bromophenyl)-2-oxo-2-(2-vinylpyrrolidin-
1-yl)ethyl)propionamide (3a). Chromatography with PE/EtOAc
6:4 f 4:6. Yield: 98%. State: yellow gum. Rf of the two dia-
stereomers: 0.48 and 0.39 (PE/EtOAc 3:7). Dr: 60:40. N-Benzyl-
N-(1-(2-iodophenyl)-2-oxo-2-(2-vinylpyrrolidin-1-yl)ethyl)propio-
namide (3b). Chromatography with PE/EtOAc 4:6 þ 1% EtOH.
Yield: 95%. State: yellow gum. Rf: 0.30 both diastereomers (PE/
EtOAc 1:1). Dr: 60:40. N-(1-(2-Bromophenyl)-2-oxo-2-(2-vinyl-
pyrrolidin-1-yl)ethyl)-N-butylpropionamide (3c). Chromatogra-
phy with PE/EtOAc 1:1 f 4:6. Yield: 99%. State: amber gum. Rf
of the two diastereomers: 0.45 and 0.35 (PE/EtOAc 1:1). Dr:
54:46. N-(1-(2-Bromo-5-fluorophenyl)-2-oxo-2-(2-vinylpyrroli-
din-1-yl)ethyl)-N-isobutylbenzamide (3d). Chromatography with
PE/EtOAc 75:25 f 65:35. Yield: 96%. State: yellow foam. Rf:
0.39 both diastereomers (PE/EtOAc 3:7). Dr: 55:45. N-(2-
Iodophenyl)-2-oxo-2-(2-vinylpyrrolidin-1-yl)ethyl)-N-isobutyl-
benzamide (3e). Chromatography with PE/EtOAc 1:1. Yield:
90%. State: yellow gum. Rf of the two diastereomers: 0.59 and
0.55 (PE/EtOAc 4:6). Dr: 54:46. N-Benzyl-N-(1-(5-bromobenzo-
[d][1,3]dioxol-6-yl)-2-oxo-2-(2-vinylpyrrolidin-1-yl)ethyl)-2-me-
thoxyacetamide (3f). Chromatography with CH2Cl2/EtOAc 4:6 f
2:8. Yield: 94%. State: very thick pale yellow oil. Rf of the two
diastereomers: 0.54 and 0.46 (CH2Cl2/EtOAc 2:8). Dr: 59:41.
N-((Furan-2-yl)methyl)-N-(1-(2-iodophenyl)-2-oxo-2-(2-vinylpyr-
rolidin-1-yl)ethyl)-2-methoxyacetamide (3g). Chromatography
with PE/EtOAc 2:8 f 1:9. Yield: 100%. State: yellow gum. Rf
of the two diastereomers: 0.51 and 0.46 (EtOAc). Dr: 52:48.
N-(1-(2-Bromo-5-fluorophenyl)-2-oxo-2-(2-vinylpyrrolidin-1-yl)-
ethyl)-N-((furan-2-yl)methyl)-2-methoxyacetamide (3h). Chro-
matography with PE/EtOAc 4:6 þ 0.5% EtOH. Yield: 95%.
State: pale yellow gum. Rf of the two diastereomers: 0.56 and
0.51 (PE/EtOAc 1:9). Dr: 51:49. N-(1-(2-Iodophenyl)-2-oxo-
2-(2-vinylpyrrolidin-1-yl)ethyl)-2-methoxy-N-phenylacetamide (3i).
Chromatography with PE/EtOAc 1:1. Yield: 95%. State: very
thick yellow oil. Rf of the two diastereomers: 0.33 and 0.25 (PE/
EtOAc 1:1). Dr: 58:42. 3-(((Benzyloxy)carbonyl)amino)-N-(1-(2-
bromo-5-fluorophenyl)-2-oxo-2-(2-vinylpyrrolidin-1-yl)ethyl)-
N-((furan-2-yl)methyl)propionamide (3j). Chromatography with
PE/EtOAc 4:6 þ 0.5% EtOH. Yield: 95%. State: ivory foam. Rf
of the two diastereomers: 0.47 and 0.43 (PE/EtOAc 4:6 þ 1%
EtOH). Dr: 57:43.
2-(2-Iodophenyl)-N-(E)-6-(((methoxycarbonyl)oxy)hex-4-en-
1-yl)-2-(N-(phenyl)methoxyacetamido))acetamide (2i). Chromato-
graphy with PE/EtOAc 1:1 þ 1% EtOH. Yield: 89%. State:
thick pale yellow oil. Rf = 0.26 (PE/EtOAc 1:1). IR: νmax
3426, 2976, 1740, 1669, 1492, 1440, 1235, 1188, 1023, 969, 925.
HR-MS: calcd for C25H29IN2O6: 580.1070; found 580.1070, 0
1
ppm. GC-MS: unsuitable for this analysis. H NMR (DMSO-
d6, temp=80°C): δ1.52 (2H, quintuplet, J= 7.1 Hz), 2.01 (2H, br
q, J = 7.2 Hz), 3.15 (2H, center of m), 3.22 (3H, s), 3.63 and 3.75
(2H, AB system, J = 14.9 Hz), 3.71 (3H, s), 4.54 (2H, dd, J=
6.3, 0.6 Hz), 5.52-5.85 (2H, m), 6.18 (1H, s), 6.82-6.89 (2H, m),
7.03 (1H, br t, J = 7.5, 1.2 Hz), 7.15-7.18 (3H, m), 7.34 (2H,
apparent br s), 7.80 (1H, dd, J = 7.8, 0.9 Hz), 8.01 (1H, br t, J=
5.2 Hz). 13C NMR (DMSO-d6, temp = 60 °C): δ 27.8 (CH2),
28.6 (CH2), 38.1 (CH2), 54.2 (CH3), 58.0 (CH3), 67.48 (CH2),
67.53 (CH), 69.8 (CH2), 103.6 (C), 123.6 (CH), 127.3 (CH),
127.7 (CH), 128.0 (2C, CH), 129.4 (CH), 129.7 (2C, CH), 130.6
(CH), 135.3 (CH), 137.5 (C), 137.6 (C), 138.8 (CH), 154.6 (C),
168.0 (C), 168.8 (C).
2-(3-(Benzyloxycarbonylamino)-2-(2-bromo-4-fluorophenyl)-
N-((furan-2-yl)methyl))propionamido)-N-(E)-6-(((methoxycarbo-
nyl)oxy)hex-4-en-1-yl)acetamide (2j). Chromatography with
PE/EtOAc 1:1 f 4:6. Yield: 72%. State: thick pale yellow oil.
Rf = 0.26 (PE/EtOAc 1:1). IR: νmax 3437, 2996, 1712, 1501,
1441, 1232, 1013, 972, 925. HR-MS: calcd for C32H35BrFN3O8
687.1592, found 687.1585, -1.0 ppm. GC-MS: unsuitable for
this analysis. 1H NMR (DMSO-d6, temp = 90 °C): δ 1.52 (2H,
quintuplet, J = 7.2 Hz), 2.03 (2H, br q, J = 7.1 Hz), 2.67-2.83
(2H, m), 2.99-3.21 (2H, m), 3.34 (2H, br q, J = 6.6 Hz), 3.71
(3H, s), 4.51 and 4.68 (2H, AB system, J = 17.7 Hz), 4.54 (2H,
dd, J = 6.0, 0.9 Hz), 5.04 (2H, s), 5.53-5.85 (3H, m), 6.00 (1H,
br s), 6.18 (1H, dd, J = 3.3, 1.8 Hz), 6.80 (1H, br s), 7.05-7.55
(9H, m), 8.02 [1H, br s; at rt: 2 signals in 78:22 ratio at 8.35 (br t,
J = 5.4 Hz) and 8.57 (br t, J = 4.8 Hz) respectively]. 13C NMR
(DMSO-d6, temp=90 °C): δ 27.5 (CH2), 28.4 (CH2), 32.8 (CH2),
36.6 (CH2), 38.0 (CH2), 41.8 (CH2, very br signal; at rt 42.1),
53.9 (CH3), 61.0 [CH, very br signal; at rt 59.72 (m) and 60.5
(M)], 64.8 (CH2), 67.2 (CH2), 106.4 (CH), 109.6 (CH), 116.3 (d,
CH, JC-F = 22.1 Hz), 116.9 (d, CH, JC-F = 24.2 Hz), 119.4 (d,
C, JC-F = 2.9 Hz), 123.1 (CH), 127.0, 127.1, 127.7 (5C, CH),
133.6 (d, CH, JC-F = 8.1 Hz), 134.8 (CH), 136.7 (C), 137.5 (br s,
C), 141.1 (C), 150.5 (CH), 154.4 (C), 155.4 (C), 162.3 (d, C,
JC-F = 243.4 Hz), 167.4 (C), 171.0 (C).
General Procedure for the Heck Cyclization. Pyrrolidine 3
(170 μmol) was dissolved in dry DMF (2 mL) in a MW vessel
equipped with a rubber septum. The solution was carefully
degassed and kept under Ar. Cs2CO3 (2 equiv) and DPPE
(10% with respect to 3) were rapidly added, and the system
was degassed. Then Pd(PPh3)4 (10%) was added, and the
suspension was degassed again. The septum was rapidly re-
moved, and the vessel was closed and heated at 120 °C for 1 h
using 150 W maximum power (see temperature and power
profiles in the Supporting Information). The crude was then
filtered over a Celite pad, and the resulting solution was diluted
with water and extracted with EtOAc. After drying and solvent
removal, the crude was purified by chromatography to give
compounds 4.
General Procedure for the SN20 Reactions. A solution of
carbonate 2 (400-500 μmol) in dry MeCN (9 mL) was carefully
degassed and kept under Ar. Then DPPE (20% with respect to
2) and Pd(PPh3)4 (10%) were added, and the reaction was stirred
at 60 °C until complete (1-2 h). The same reaction can be
successfully performed in the presence of 3% catalyst (and 6%
DPPE) without affecting the yield, but the reaction speed is
(6R*,11aS*)-6-(N-Benzylpropionamido)-11-methylene-2,3,11,
11a-tetrahydro-1H-benzo[d]pyrrolo[1,2-a]azepin-5(6H)-one (cis-
4a). Chromatography with PE/EtOAc 1:1 f EtOAc þ 1%
EtOH. Yield: 31% from 2a, 44% from 2b. State: yellow foam.
Crystallization from i-Pr2O/CH2Cl2 afforded pale yellow crys-
tals. Mp: 130.3-131.6 °C dec. Rf = 0.54 (PE/EtOAc 2:8). IR:
νmax 2999, 1641, 1413, 1248, 1184, 1026. HR-MS: calcd for
5140 J. Org. Chem. Vol. 75, No. 15, 2010

Riva et al.
JOCArticle
C24H26N2O2 374.1994, found 374.1980, -3.7 ppm. GC-MS: tR
11.94; m/z 374 (Mþ, 4.6), 317 (12), 227 (26), 213 (100), 212 (16),
211 (47), 210 (5.6), 196 (5.5), 184 (25), 183 (37), 182 (15), 156
(5.8), 155 (7.1), 143 (5.2), 142 (7.9), 141 (6.2), 128 (7.9), 115 (12),
106 (7.7), 91 (62), 65 (8.8), 57 (13). Note: Benzylic CHN as the cis
diastereomer is very difficult to identify because it is usually a
very broad signal, hardly distinguishable from the baseline. For
this reason, it is necessary to perform proton spectra in DMSO-
IR: νmax 3013, 2890, 1724, 1638, 1509, 1472, 1415, 1374, 1231,
1048, 927. HR-MS: calcd for C21H28N2O2 340.2151, found
340.2141, -2.9 ppm. GC-MS: tR 10.63; m/z 340 (Mþ, 4.5), 284
(8.0), 283 (36), 227 (11), 214 (16), 213 (100), 212 (24), 211 (74), 210
(10), 200 (5.1), 198 (5.0), 196 (5.8), 185 (8.6), 184 (59), 183 (91), 182
(32), 170 (8.8), 169 (6.1), 168 (11), 167 (12), 157 (6.3), 156 (14), 155
(22), 154 (11), 153 (9.3), 144 (7.1), 143 (12), 142 (19), 141 (18), 130
(15), 129 (13), 128 (20), 127 (7.9), 116 (10), 115 (30), 103 (5.7), 77
(6.1), 70 (7.2), 57 (39), 56 (13), 41 (22), 39 (6.3). 1H NMR (DMSO-
d6): δ 0.66 (3H, t, J = 7.4 Hz), 0.86-1.09 (2H, m), 1.02 (3H, t, J =
7.5 Hz), 1.20-1.33 (2H, m), 1.53-1.76 (3H, m), 2.22-2.48 (4H,
m), 3.05 (1H, dt, J = 9.9, 7.2 Hz), 3.24 (1H, center of m),
3.35-3.45 (1H, m), 4.26 (1H, br t, J = 7.4 Hz), 4.77 (1H, br s),
5.18 (1H, br s), 5.21 (1H, br s), 7.29-7.44 (4H, m). 13C NMR
(DMSO-d6): δ 9.7 (CH3), 13.3 (CH3), 19.2(CH2), 21.7 (CH2), 26.2
(CH2), 29.3(CH2), 36.9(CH2), 44.3 (CH2), 47.3 (CH2), 59.4 (CH),
66.8 (CH), 114.0 (CH2), 128.3, 129.1, 129.4, 129.5 (4C, CH), 132.9
(C), 137.3 (C), 149.0 (C), 167.4 (C), 174.1 (C).
1
d6 at 80-90 °C. H NMR (DMSO-d6, temp = 90 °C): δ 0.90
(3H, t, J=7.4 Hz), 1.78-1.88 (2H, m), 1.94-2.40 (2H, m), 2.14
(2H, center of m), 3.21 (1H, dt, J=11.4, 7.6 Hz), 3.51 (1H, ddd,
J=12.3, 7.3, 5.2 Hz), 4.79 (1H, t, J=7.2 Hz), 4.93 and 5.25 (2H,
AB system, J=16.2 Hz), 5.35 (1H, d, J=0.9 Hz), 5.37 (1H, d,
J = 0.9 Hz), 6.47 (1H, br s), 7.24-7.38 (9H, m). 13C NMR
(DMSO-d6, temp = 90 °C): δ 8.6 (CH3), 21.5 (CH2), 26.3 (CH2),
33.2 (CH2), 45.8 (CH2), 50.5 (CH2), 59.6 (very br signal, CH),
60.0 (CH), 113.6 (CH2), 124.2, 125.6, 126.4, 127.0, 127.3, 127.5,
127.7 (9C, CH), 135.6 (C), 137.1 (C), 139.3 (C), 147.3 (C), 166.9
(C), 174.9 (C).
(6R*,11aS*)-8-Fluoro-6-(N-isobutylbenzamido)-11-methylene-
2,3,11,11a-tetrahydro-1H-benzo[d]pyrrolo[1,2-a]azepin-5(6H)-
one (cis-4d). Chromatography with PE/EtOAc 6:4 f 1:9 af-
forded a mixture of cis-4d and 6d. These two compounds were
nearly completely overlapped in TLC, and therefore, a second
chromatography with PE/CH2Cl2/Me2CO 45:45:10 was neces-
sary. Only traces of cis-4d were isolated, and for this reason, only
a partial characterization was performed: anyway, due to very
strong spectroscopic analogies with other cis-4 derivatives, the
hypothesized structure was reasonably confirmed. State: yellow
gum. Rf = 0.37 (PE/CH2Cl2/Me2CO 45:45:10). GC-MS: tR
11.76; m/z 406 (Mþ, 1.9), 301 (17), 232 (10), 231 (62), 230 (10),
229 (36), 202 (18), 201 (29), 160 (5.1), 133 (8.7), 106 (8.1), 105
(6R*,11aR*)-6-(N-Benzylpropionamido)-11-methylene-2,3,11,
11a-tetrahydro-1H-benzo[d]pyrrolo[1,2-a]azepin-5(6H)-one (trans-
4a). Chromatography with PE/EtOAc 1:1 f EtOAc þ 1% EtOH.
Yield: 38% from 2a, 37% from 2b. State: white solid. Crystallization
from i-Pr2O/CH2Cl2 afforded white crystals. Mp: 160.1-162.9 °C
dec. Rf = 0.21 (PE/EtOAc 2:8). IR: νmax 2972, 2881, 1641, 1413,
1189, 1027. HR-MS: calcd for C24H26N2O2 374.1994, found
374.1982, -3.3 ppm. GC-MS: tR 11.85; m/z 374 (Mþ, 2.7), 317
(16), 290 (6.2), 227 (22), 214 (15), 213 (82), 212 (6.2), 211 (20), 184
(15), 183 (5.8), 170(6.5), 168(7.6), 156(6.6), 144(12), 143(7.5), 142
(22), 141 (7.4), 130 (12), 129 (11), 128 (9.3), 117 (5.5), 116 (12), 115
(15), 106 (13), 92 (8.8), 91 (100), 70 (27), 65 (14), 57 (24). 1H NMR
(CDCl3): δ 1.19 (3H, t, J = 7.5 Hz), 1.71-1.93 (3H, m), 2.28-2.35
(1H, m), 2.45 (2H, center of m), 3.29 (1H, dt, J = 8.6, 7.8 Hz), 3.68
and 4.78 (2H, AB system, J= 17.2 Hz), 3.76 (1H, center of m), 4.40
(1H, br t, J = 8.0 Hz), 4.91 (1H, s), 5.16 (1H, d, J = 1.5 Hz), 5.31
1
(100), 77 (55), 51 (5.5), 41 (9.3). H NMR (DMSO-d6): δ 0.70
(3H, d, J = 6.6 Hz), 0.72 (3H, d, J = 6.6 Hz), 1.70 (1H, center of
m), 1.78-1.92 (2H, m), 1.96-2.08 (1H, m), 2.22-2.32 (1H, m),
3.21-3.58 (4H, m), 4.72 (1H, very br s), 5.33 (2H, br s), 5.74 (1H,
br s), 7.09-7.54 (8H, m).
(1H, d, J = 1.2 Hz), 6.83-6.89 (3H, m), 7.11-7.36 (6H, m). 13
C
NMR (CDCl3): δ 9.6 (CH3), 22.0 (CH2), 27.2 (CH2), 37.4 (CH2),
47.7 (CH2), 48.9 (CH2), 60.2 (CH), 68.1 (CH), 113.5 (CH2), 126.3,
127.5, 128.4, 128.8, 129.1, 129.5, 130.0 (9C, CH), 132.7 (C), 136.1
(C), 137.2 (C), 149.7 (C), 168.1 (C), 175.3 (C).
(6R*,11aR*)-8-Fluoro-6-(N-isobutylbenzamido)-11-methylene-
2,3,11,11a-tetrahydro-1H-benzo[d]pyrrolo[1,2-a]azepin-5(6H)-one
(trans-4d). Chromatography with PE/Me2CO 7:3 f 68:32. Yield:
26%. State: yellow gum. Rf = 0.30 (PE/Me2CO 7:3). IR: νmax
2963, 1636, 1400, 1193, 1026, 701. HR-MS: calcd for C25H27-
FN2O2 406.2057, found 406.2062, þ1.3 ppm. GC-MS: tR 11.79;
m/z 406 (Mþ, 0.21), 232 (6.9), 231 (45), 230 (6.9), 229 (25), 202
(14), 201 (23), 200 (9.6), 133 (8.4), 106 (7.7), 105 (100), 77 (48), 41
(6.6). 1H NMR (DMSO-d6, temp = 80 °C): δ 0.46 (3H, d, J = 6.6
Hz), 0.63 (3H, d, J = 6.6 Hz), 1.58-1.92 (4H, m), 2.35-2.43 (1H,
m), 2.56 (1H, dd, J=14.7, 5.1 Hz), 3.13 (1H, dd, J=14.7, 4.8 Hz),
3.13-3.29 (1H, m), 3.42 (1H, center of m), 4.55 (1H, br dd, J=8.7,
6.3 Hz), 4.98 (1H, s), 5.36 (1H, d, J = 1.8 Hz), 5.40 (1H, d, J=1.1
Hz), 7.22 (1H, dt, J = 8.7, 2.7 Hz), 7.37 (1H, dd, J = 8.4, 5.7 Hz),
7.40 (1H, dt, J = 9.3, 2.7 Hz), 7.43-7.50 (5H, m). 13C NMR
(DMSO-d6): δ 19.1 (CH3), 19.6 (CH3), 21.3 (CH2), 25.9 (CH),
37.2 (CH2), 47.5 (CH2), 55.0 (br signal, CH2), 60.0 (CH), 65.9
(CH), 114.4 (CH2), 116.0 (d, CH, JC-F = 20.9 Hz), 116.3 (d, CH,
JC-F = 23.1 Hz), 127.7 (2C, CH), 128.5 (2C, CH), 130.4 (CH),
131.4 (d, CH, JC-F = 8.2 Hz), 133.0 (d, C, JC-F = 3.2 Hz), 135.3
(6R*,11aS*)-6-(N-Butylpropionamido)-11-methylene-2,3,11,
11a-tetrahydro-1H-benzo[d]pyrrolo[1,2-a]azepin-5(6H)-one (cis-
4c). Chromatography with PE/EtOAc 4:6 f EtOAc/EtOH 9:1.
Yield: 25%. State: yellow gum. Rf = 0.72 (EtOAc þ 3% EtOH).
IR: νmax 3005, 1724, 1628, 1504, 1419, 1374, 1225, 1039, 923.
HR-MS: calcd for C21H28N2O2: 340.2151, found 340.2146, -1.5
ppm. GC-MS: tR 10.61; m/z 340 (Mþ, 4.5), 284 (7.9), 283 (36),
227 (11), 214 (17), 213 (100), 212 (24), 211 (76), 210 (11), 200
(5.5), 196 (5.4), 185 (9.2), 184 (59), 183 (88), 182 (31), 170 (8.8),
169 (5.9), 168 (11), 167 (12), 157 (6.1), 156 (13), 155 (21), 154
(9.7), 153 (8.6), 144 (6.7), 143 (12), 142 (19), 141 (16), 130 (13),
129 (13), 128 (19), 127 (6.9), 116 (9.0), 115 (29), 103 (5.2), 77
1
(5.8), 70 (6.8), 57 (35), 56 (12), 41 (19). H NMR (DMSO-d6,
temp = 90 °C): δ 0.89 (3H, t, J = 7.4 Hz), 0.96 (3H, t, J = 7.4
Hz), 1.29 (2H, hexuplet, J = 7.4 Hz), 1.50 (1H, center of m),
1.66-1.79 (1H, m), 1.81-1.93 (2H, m), 1.99-2.39 (2H, m), 2.20
(2H, center of m), 3.30 (1H, dt, J = 11.7, 7.5 Hz), 3.47-3.69
(3H, m), 4.77 (1H, t, J = 7.1 Hz), 5.37 (1H, d, J = 1.5 Hz), 5.39
(1H, d, J = 0.6 Hz), 6.26 (1H, br s), 7.19-7.40 (4H, m). 13C
NMR (DMSO-d6, temp = 90 °C): δ 8.9 (CH3), 13.0 (CH3), 19.3
(CH2), 21.7 (CH2), 26.0 (CH2), 31.0 (CH2), 32.4 (CH2), 45.9
(CH2), 47.3 (CH2), 59.5 (CH), 60.7 (CH), 113.0 (CH2), 125.0,
126.9, 127.5, 127.6 (4C, CH), 135.4 (C), 137.5 (C), 147.1 (C),
166.8 (C), 173.9 (C).
(6R*,11aR*)-6-(N-Butylpropionamido)-11-methylene-2,3,11,
11a-tetrahydro-1H-benzo[d]pyrrolo[1,2-a]azepin-5(6H)-one (trans-
4c). Chromatography with PE/EtOAc 4:6 f EtOAc/EtOH 9:1.
Yield: 43%. State: yellow gum. Rf = 0.19 (EtOAc þ 3% EtOH).
(d, C, JC-F = 8.1 Hz), 135.4 (C), 147.8 (C), 161.6 (d, C, JC-F
245.6 Hz), 166.1 (C), 172.0 (C).
=
(6R*,11aS*)-6-(N-Isobutylbenzamido)-11-methylene-2,3,11,
11a-tetrahydro-1H-benzo[d]pyrrolo[1,2-a]azepin-5(6H)-one (cis-
4e). Chromatography with PE/EtOAc 6:4 f EtOAc. Yield:
18%. State: yellow gum. Rf =0.62 (PE/EtOAc 3:7). IR: νmax
2960, 2868, 1627, 1399, 1261, 1026, 907. HR-MS: calcd for
C25H28N2O2 388.2151, found 388.2146, þ1.3 ppm. GC-MS: tR
11.79; m/z: 388 (Mþ, 0.36), 283 (12), 281 (6.3), 214 (8.8), 213 (54),
212 (11), 211 (37), 207 (6.9), 184 (26), 183 (33), 182 (15), 155
(6.9), 142 (6.6), 141 (6.5), 128 (7.5), 115 (12), 106 (7.7), 105 (100),
104 (7.8), 77 (64), 57 (5.3), 51 (6.3), 41 (8.8). 1H NMR (DMSO-d6,
J. Org. Chem. Vol. 75, No. 15, 2010 5141

Riva et al.
JOCArticle
temp=80 °C): δ 0.70 (3H, d, J=6.6 Hz), 0.74 (3H, d, J=6.6 Hz),
1.68-2.05 (4H, m), 3.25 (1H, center of m), 3.30 (1H, dt,
J=15.6, 7.8 Hz), 3.33 (1H, dd, J=13.8, 8.1 Hz), 3.44-3.56 (1H,
m), 3.59 (1H, dd, J=13.8, 6.6 Hz), 4.54 (1H, br t, J=7.5 Hz),
5.26 (1H, s), 5.31 (1H, d, J=1.2 Hz), 5.85 (1H, s), 7.26-7.44
(9H, m). 13C NMR (DMSO-d6): δ 20.0 (2C, CH3), 22.1 (CH2),
27.6 (CH), 33.1 (CH2), 46.9 (CH2), 55.3 (very br signal, CH2),
60.2 (CH), 62.5 (very br signal, CH), 113.9 (CH2), 125.8, 126.5,
127.5, 127.9, 128.8, 128.3 (9C, CH), 129.2 (C), 135.2 (C), 137.2
(C), 147.4 (C), 165.9 (C), 172.7 (C).
(6R*,11aR*)-6-(N-Isobutylbenzamido)-11-methylene-2,3,11,
11a-tetrahydro-1H-benzo[d]pyrrolo[1,2-a]azepin-5(6H)-one (trans-
4e). Chromatography with PE/EtOAc 6:4 f EtOAc. Yield: 43%.
State: yellow gum. Rf = 0.22 (PE/EtOAc 3:7). IR: νmax 3003, 1630,
1405, 1185, 1027, 894. HR-MS: calcd for C25H28N2O2 388.2151,
found 388.2155, þ1.0 ppm. GC-MS: tR 11.92; m/z 388 (Mþ, 1.2),
283 (17), 281 (5.1), 214 (13), 213 (75), 212 (14), 211 (51), 210
(6.1), 185 (5.1), 184 (33), 183 (41), 182 (16), 167 (5.2), 155 (8.3), 143
(5.0), 142 (7.4), 141 (7.1), 128 (8.1), 115 (12), 106 (7.9), 105 (100),
104 (6.0), 77 (60), 51 (5.6), 41 (8.2). 1H NMR (DMSO-d6):
δ 0.34 (3H, d, J = 6.6 Hz), 0.59 (3H, d, J = 6.3 Hz), 1.51-1.79
(4H, m), 2.38 (1H, dd, J= 16.5, 5.7 Hz), 2.42 (1H, dd, J= 14.7, 3.9
Hz), 3.00-3.16 (2H, m), 3.40 (1H, br t, J=13.0Hz), 4.50(1H, brt,
J=7.6 Hz), 4.89 (1H, s), 5.38 (1H, s), 5.43 (1H, s), 7.34-7.66
(9H, m). 13C NMR (DMSO-d6): δ 19.0 (CH3), 19.6 (CH3), 21.4
(CH2), 26.0 (CH), 37.3 (CH2), 47.4 (CH2), 54.9 (br signal, CH2),
60.0 (CH), 66.6 (br signal, CH), 114.2 (CH2), 127.7 (2C, CH),
128.3 (CH), 128.5 (2C, CH), 129.3 (CH), 129.4 (CH), 129.5 (CH),
130.3 (CH), 132.7 (C), 135.6 (C), 136.7 (C), 149.0 (C), 166.6 (C),
172.0 (C).
(6R*,11aS*)-6-(N-Benzylmethoxyacetamido)-11-methylene-
8,9-(methylenedioxy)-2,3,11,11a-tetrahydro-1H-benzo[d]pyrrolo-
[1,2-a]azepin-5(6H)-one (cis-4f). Chromatography with CH2Cl2/
Me2CO 9:1 f 7:3 þ 0.5% EtOH. Yield: 30%. State: colorless
oil. Rf = 0.38 (CH2Cl2/Me2CO 9:1). IR: νmax 2965, 2886, 1648,
1473, 1418, 1251, 1119, 1027, 931. HR-MS: calcd for C25H26-
N2O5 434.1842, found 434.1825, -3.9 ppm. GC-MS: tR 14.41
(diastereomeric mixture of cis- and trans-4f); m/z 361 (Mþ - 73,
3.2), 283 (20), 281 (7.6), 257 (21), 256 (8.9), 255 (33), 254 (5.0),
229 (5.1), 228 (28), 227 (26), 226 (16), 214 (5.1), 207 (10), 186
(10), 155 (5.3), 128 (6.6), 115 (9.5), 102 (5.1), 92 (9.3), 91 (100), 89
(7.3), 77 (12), 65 (15), 51 (5.2), 45 (58), 39 (6.0). 1H NMR
(DMSO-d6, temp = 80 °C): δ 1.73-2.03 (3H, m), 2.29 (1H, cen-
ter of m), 3.18-3.30 (1H, m), 3.22 (3H, s), 3.49 (1H, ddd, J=
12.0, 7.8, 4.5 Hz), 3.84 and 4.02 (2H, AB system, J=14.2 Hz),
4.68 (1H, br t, J=7.4 Hz), 4.80 and 5.16 (2H, AB system, J=16.0
Hz), 5.30 (1H, d, J=1.2 Hz), 5.33 (1H, d, J = 2.0 Hz), 5.97 and
6.00 (2H, AB system, J = 0.9 Hz), 6.22 (1H, br s), 6.76 (1H, s),
6.85 (1H, s), 7.16-7.30 (5H, m). 13C NMR (DMSO-d6, temp=
60 °C): δ 21.7 (CH2), 33.6 (CH2), 46.2 (CH2), 49.6 (CH2), 58.1
(CH3), 59.4 (CH), 60.3 (CH), 70.6 (CH2), 101.0 (CH2), 105.2
(CH), 108.2 (CH), 113.8 (CH2), 126.0 (CH), 126.5 (2C, CH),
127.5 (2C, CH), 129.3 (C), 131.1 (C), 138.8 (C), 146.3 (C), 146.9
(C), 147.1 (C), 166.7 (C), 170.7 (C).
6.97-7.00 (2H, m), 7.22-7.34 (3H, m). 13C NMR (DMSO-d6):
δ 21.6 (CH2), 36.8 (CH2), 47.1 (CH2), 47.2 (CH2), 58.4 (CH3),
59.2 (CH), 67.2 (CH), 70.2 (CH2), 101.5 (CH2), 109.6 (CH),
110.0 (CH), 114.3 (CH2), 125.3 (C), 126.1 (2C, CH), 127.1 (CH),
128.5 (2C, CH), 131.2 (C), 136.7 (C), 146.8 (C), 147.99 (C),
148.04 (C), 166.5 (C), 170.3 (C).
(6R*,11aS*)-8-Fluoro-6-(N-((furan-2-yl)methyl)methoxyacet-
amido)-11-methylene-2,3,11,11a-tetrahydro-1H-benzo[d]pyrrolo-
[1,2-a]azepin-5(6H)-one (cis-4h). Chromatography with PE/
Me2CO 7:3 f 3:7. The isolated product was shown to be a 61:39
(1H NMR) mixture of cis-4h and 5h (8-Fluoro-6-(N-((furan-2-yl)-
methyl)methoxyacetamido)-11-methyl-2,3-dihydro-1H-benzo-
[d]pyrrolo[1,2-a]azepin-5(6H)-one). We were not able to sepa-
rate them, and therefore, they have been characterized as a
mixture. Yield: 10% (cis-4h); 6% (5h). State: yellow gum. Rf =
0.50 (PE/Me2CO 65:35). IR: νmax 2970, 2881, 1638, 1420, 1260,
1025, 920. HR-MS: calcd for C22H23FN2O4 398.1642, found
398.1631, -2.8 ppm. GC-MS: (a) tR 11.44; m/z 325 (Mþ - 73,
6.5), 318 (9.8), 232 (14), 231 (88), 230 (13), 229 (14), 214 (9.0), 202
(19), 201 (21), 200 (13), 168 (32), 160 (5.7), 159 (6.7), 146 (7.5),
133 (14), 108 (13), 82 (7.3), 81 (100), 70 (6.5), 53 (25), 45 (72), 41
(5.8); (b) tR 11.66; m/z 398 (Mþ, 9.7), 317 (30), 289 (5.7), 258 (17),
257 (100), 245 (5.5), 232 (8.5), 231 (50), 230 (7.6), 229 (16), 202
(28), 201 (6.2), 200 (6.8), 188 (5.0), 174 (7.3), 168 (8.1), 146 (5.2),
133 (7.2), 81 (56.4), 53 (12), 45 (38). 1H NMR (DMSO-d6,
temp = 80 °C): δ 1.78-1.96 (2H, m, 4h þ 5h), 2.02-2.14 (1H,
m, 4h), 2.18 (3H, s, 5h), 2.32 (1H, center of m, 4h), 2.74 (2H,
center of m, 5h), 3.25 (3H, s, 4h), 3.29 (3H, s, 5h), 3.33 (center of
m) and 3.49-3.71 (m) (2H, 4h þ 5h), 4.00 and 4.03 (2H, AB
system, J = 14.1 Hz, 4h), 4.07 (2H, s, 5h), 4.25 and 4.71 (2H, AB
system, J = 16.8 Hz, 5h), 4.72 (1H, br t, J = 6.6 Hz, 4h), 4.87 and
4.87 (2H, AB system, J = 16.6 Hz, 4h), 5.19 (1H, br s, 5h), 5.37
(1H, d, J = 1.0 Hz, 4h), 5.40 (1H, br s, 4h), 6.12 (1H, br dd, J =
3.3, 0.6 Hz, 5h), 6.15 (1H, br s, 4h), 6.27 (1H, br dd, J = 3.0, 0.6
Hz, 4h), 6.35 (1H, dd, J = 3.0, 1.8 Hz, 4h), 6.36 (1H, dd, J = 3.0,
1.8 Hz, 5h), 6.89 (1H, dd, J = 10.8, 2.4 Hz, 4h), 7.02 (1H, dd, J =
10.2, 2.7 Hz, 5h), 7.07 (1H, dt, J = 9.0, 2.7 Hz, 4h), 7.20 (1H, dt,
J = 8.7, 2.7 Hz, 5h), 7.41 (1H, dd, J = 8.4, 6.0 Hz, 4h), 7.51 (1H,
dd, J = 1.8, 0.9 Hz, 4h þ 5h), 7.52 (1H, dd, J = 9.0, 6.0 Hz, 5h).
13C NMR (DMSO-d6): δ 19.0 (CH2), 20.2 (CH2), 22.4 (CH3, 5h),
29.8 (CH2, 5h), 32.4 (CH2, 4h), 43.6 (CH2), 46.5 (CH2), 48.2
(CH2), 58.30 (CH3), 58.34 (CH3), 59.1 (2C, CH), 70.5 (CH2),
70.6 (CH2), 107.7 (CH), 108.1 (C, 5h), 108.2 (CH), 110.44 (CH),
110.47 (CH), 112.1, 112.4, 114.1, 114.4, 114.8, 115.0 (2C, CH; it
was not possible to calculate JC-F), 113.7 (CH2, 4h), 127.7 (d,
CH, JC-F = 8.6 Hz), 130.5 (d, CH, JC-F = 8.2 Hz), 133.7 (d, C,
J
C-F = 3.0 Hz), 133.8 (C, 5h), 136.6, 136.7, 137.0, 137.2 (C; it
was not possible to calculate JC-F), 142.2 (CH), 142.3 (CH),
145.7 (C), 151.4 (C, 4h), 161.3 (d, C, JC-F = 243.3 Hz), 161.8 (d,
C, JC-F = 242.8 Hz), 165.8 (C), 170.62 (C), 170.64 (C).
(6R*,11aR*)-8-Fluoro-6-(N-((furan-2-yl)methyl)methoxyacet-
amido)-11-methylene-2,3,11,11a-tetrahydro-1H-benzo[d]pyrrolo-
[1,2-a]azepin-5(6H)-one (trans-4h). Chromatography with PE/
Me2CO 7:3 f 3:7. Yield: 25%. State: yellow gum. Rf = 0.29 (PE/
Me2CO 6:4). IR: νmax 3044, 2975, 2878, 1640, 1413, 1242, 1008, 918.
HR-MS: calcd for C22H23FN2O4 398.1642, found 398.1636, -1.5
ppm. GC-MS: tR 11.46; m/z 398 (Mþ, 0.23), 317 (5.7), 257 (5.2),
231 (100), 230 (14), 229 (15), 216 (5.0), 214 (9.3), 202 (18), 201 (20),
200 (12), 168 (26), 159 (5.4), 146 (5.8), 133 (10), 108 (9.3), 82 (5.4),
81 (77), 53 (20), 45 (57). 1H NMR (DMSO-d6, temp = 80 °C): δ
1.62-1.86 (3H, m), 2.30-2.38 (1H, m), 3.14-3.25 (1H, m), 3.40-
3.49 (1H, m), 3.35 (3H, s), 3.73 and 4.56 (2H, AB system, J=17.1
Hz), 4.14 and 4.31 (2H, AB system, J = 14.7 Hz), 4.42 (1H, center
of m), 4.75 (1H, s), 5.26 (1H, d, J=1.5 Hz), 5.28 (1H, d, J=1.5 Hz),
6.09 (1H, dd, J = 3.3, 0.9 Hz), 6.38 (1H, dd, J = 3.3, 1.8 Hz), 6.99
(1H, dd, J=9.3, 2.7Hz), 7.22(1H, dt, J= 8.4, 2.7 Hz), 7.36 (1H, dd,
J = 8.4, 6.0 Hz), 7.55 (1H, dd, J=1.8, 0.6 Hz). 13C NMR (DMSO-
d6): δ 21.5 (CH2), 36.5 (CH2), 40.7 (CH2), 47.3 (CH2), 58.5 (CH3),
(6R*,11aR*)-6-(N-Benzylmethoxyacetamido)-11-methylene-
8,9-(methylenedioxy)-2,3,11,11a-tetrahydro-1H-benzo[d]pyrrolo-
[1,2-a]azepin-5(6H)-one (trans-4f). Chromatography with CH2-
Cl2/Me2CO 9:1 f 7:3 þ 0.5% EtOH. Yield: 33%. State: color-
less oil. Rf = 0.32 (CH2Cl2/Me2CO 8:2). IR: νmax 3013, 2888,
1638, 1473, 1423, 1324, 1197, 1025, 922. HR-MS: calcd for
C25H26N2O5 434.1842, found 434.1820, -5.0 ppm. GC-MS:
1
see compound cis-4f. H NMR (DMSO-d6, temp=80 °C): δ
1.55-1.86 (3H, m), 2.27-2.37 (1H, m), 3.19 (1H, ddd, J=11.7,
9.9, 7.2 Hz), 3.30 (3H, s), 3.42 (1H, ddd, J=11.7, 8.7, 3.0 Hz),
3.85 and 4.56 (2H, AB system, J = 17.4 Hz), 3.96 and 4.21 (2H,
AB system, J=14.7 Hz), 4.41 (1H, center of m), 4.82 (1H, br s),
5.24 (1H, d, J = 1.2 Hz), 5.31 (1H, d, J = 1.2 Hz), 5.99 and
6.00 (2H, AB system, J = 0.9 Hz), 6.46 (1H, s), 6.88 (1H, s),
5142 J. Org. Chem. Vol. 75, No. 15, 2010

Riva et al.
JOCArticle
59.6 (CH), 66.9 (CH), 70.2 (CH2), 108.1 (CH), 110.4 (CH), 114.6
(CH2), 116.3 (d, CH, JC-F = 20.7 Hz), 116.6 (d, CH, JC-F = 22.9
Hz), 131.2 (d, CH, JC-F = 8.2 Hz), 133.4 (d, CH, JC-F = 3.2 Hz),
134.3 (d, C, JC-F=7.9 Hz), 143.0 (CH), 147.3 (C), 149.5 (C),
161.4 (d, C, JC-F = 244.3 Hz), 165.8 (C), 170.6 (C).
(Z)-8-Fluoro-6-(N-isobutylbenzamido)-1,2,3,12a-tetrahydro-
benzo[e]pyrrolo[1,2-a]azocin-5(6H)-one (6d). Chromatography
with PE/CH2Cl2/Me2CO 45:45:10. Yield: 20%. State: yellow gum.
Rf = 0.37 (PE/CH2Cl2/Me2CO 45:45:10). The relative configura-
tion of the stereogenic centers was not assigned. IR: νmax 3004, 1631,
1254, 1191, 1027. HR-MS: calcd for C25H27FN2O2 406.2057, found
406.2050, -1.7 ppm. GC-MS: tR 11.85; m/z 406 (Mþ, 2.4), 322
(6.5), 301 (7.8), 245 (5.9), 231 (17), 229 (13), 160 (9.6), 134 (6.1), 133
(6R*,11aS*)-11-Methylene-6-(N-phenylmethoxyacetamido)-
2,3,11,11a-tetrahydro-1H-benzo[d]pyrrolo[1,2-a]azepin-5(6H)-
one (cis-4i). Chromatography with PE/CH2Cl2/Me2CO/MeOH
15:5:4:1. Yield: 24%. State: colorless oil. Rf = 0.38 (PE/CH2Cl2/
Me2CO/MeOH 15:5:4:1). IR: νmax 2992, 2879, 1659, 1413, 1268,
1123, 1024, 916. HR-MS: calcd for C23H24N2O3 376.1787,
found 376.1773, -3.7 ppm. GC-MS: tR 11.87; m/z 376 (Mþ,
6.9), 332 (8.1), 331 (33), 303 (14), 219 (5.0), 218 (5.3), 213 (6.2),
212 (23), 211 (100), 210 (7.9), 206 (7.5), 204 (5.3), 185 (7.6), 184
(57), 183 (80), 182 (28), 168 (5.3), 167 (8.1), 156 (5.1), 155 (9.2),
154 (8.7), 153 (5.8), 143 (5.3), 142 (9.7), 141 (16), 135 (14), 129
(8.8), 128 (16), 127 (5.7), 116 (5.8), 115 (24), 106 (6.2), 92 (5.2), 91
1
(6.1), 106 (7.9), 105 (100), 77 (40), 70 (6.5), 41 (8.0). H NMR
(DMSO-d6, temp = 80 °C): δ 0.60 (3H, d, J = 6.9 Hz), 0.68 (3H, d,
J=6.6Hz), 1.48(1H, centerofm), 1.71(2H, centerofm), 1.89(1H,
dt, J= 12.6, 6.3 Hz), 2.36 (1H, center of m), 3.01-3.14 (1H, m), 3.38
(1H, dd, J = 14.4, 6.9 Hz), 3.48 (1H, dt, J = 11.7, 6.8 Hz), 3.74 (1H,
dd, J = 14.4, 7.5 Hz), 4.98 (1H, center of m), 5.89 (1H, dd, J= 15.3,
2.1Hz), 6.09(1H, brs), 6.55(1H, dd, J= 13.2, 2.7 Hz), 7.06 (1H, dt,
J = 8.7, 2.7 Hz), 7.25 (1H, dd, J = 9.9, 2.7 Hz), 7.28 (1H, dt, J =
8.7, 6.0 Hz), 7.34-7.59 (5H, m). 13C NMR (DMSO-d6): δ 19.4
(CH3), 19.6 (CH3), 22.6 (CH2), 27.6 (CH), 34.2 (CH2), 46.6 (CH2),
54.8 (CH2), 57.3 (CH), 59.3 (CH), 112.4 (d, CH, JC-F = 23.1 Hz),
114.2 (d, CH, JC-F = 21.4 Hz), 126.7 (CH), 128.4 (4C, CH), 129.5
(d, C, JC-F = 2.8 Hz), 130.6 (CH), 132.7 (d, CH, JC-F = 8.2 Hz),
135.9 (d, C, JC-F = 10.5 Hz), 136.0 (CH), 138.1 (C), 161.3 (d, C,
1
(5.5), 77 (22), 51 (8.2), 45 (57), 41 (5.4). H NMR (DMSO-d6,
temp = 80 °C) (cis-4i contains a small amount of 6i (5-7%),
that cannot be separated by chromatography): δ 1.65-2.18 (4H,
m), 3.20 (3H, s), 3.41 (1H, dt, J = 7.8, 6.0 Hz), 3.54 (1H, ddd,
J = 12.3, 8.7, 4.5 Hz), 3.73 (2H, s), 4.48 (1H, t, J = 7.0 Hz), 5.07
(1H, s), 5.17 (1H, d, J = 1.2 Hz), 6.39 (1H, s), 7.10-7.38 (9H,
m). 13C NMR (DMSO-d6): δ 22.1 (CH2), 31.2 (CH2), 46.9
(CH2), 58.1 (CH3), 59.2 (CH), 65.3 (CH), 70.1 (CH2), 112.7
(CH2), 127.3 (CH), 127.6 (CH), 127.8 (CH), 128.0 (CH), 128.1
(CH), 128.5 (2C, CH), 129.1 (2C, CH), 133.4 (C), 139.1 (C),
140.7 (C), 146.2 (C), 165.6 (C), 168.5 (C).
JC-F = 243.6 Hz), 166.9 (C), 174.6 (C).
General Procedure for the One-Pot SN20-Heck Cyclization.
The same procedure described above for the Heck cyclization
was followed, starting this time from Ugi derivative 2. The same
type and amount of solvent, ligand and catalyst were employed,
with the exception of Cs2CO3. Finally, the closed vessel was
heated at 120 °C for 1 h using 150 W maximum power (see
temperature and power profiles in the Supporting Information).
Then Cs2CO3 (2 equiv) was rapidly added, and the vessel was
heated again under the same conditions for 1 h (the temperature
profile is the same as in the Heck reaction). The final workup
was the same as reported for the Heck cyclization.
(6R*,11aR*)-11-Methylene-6-(N-phenylmethoxyacetamido)-
2,3,11,11a-tetrahydro-1H-benzo[d]pyrrolo[1,2-a]azepin-5(6H)-one
(trans-4i). Chromatography with PE/CH2Cl2/Me2CO/MeOH
15:5:4:1. Yield: 41%. State: colorless oil. Rf = 0.30 (PE/CH2Cl2/
Me2CO/MeOH 15:5:4:1). IR: νmax 2972, 2876, 1674, 1434, 1188,
1124, 1023, 905. HR-MS: calcd for C23H24N2O3 376.1787, found
376.1779, -2.1 ppm. GC-MS: tR 11.82; m/z 376 (Mþ, 5.4), 332
(6.7), 331 (28), 303 (12), 213 (6.5), 212 (22), 211 (100), 210 (7.7),
206 (6.0), 185 (7.8), 184 (57.7), 183 (84), 182 (29), 168 (5.2), 167
(7.7), 155 (9.3), 154 (8.3), 153 (5.4), 143 (5.4), 142 (9.0), 141 (16),
135 (13), 129 (8.6), 128 (16), 116 (5.6), 115 (24), 106 (6.6), 91 (5.6),
77 (22), 51 (8.4), 45 (57), 41 (5.7). 1H NMR (DMSO-d6, temp=
80 °C): δ 1.61-1.98 (3H, m), 2.35 (1H, center of m), 3.21 (3H, s),
3.24-3.31 (1H, m), 3.52 and 3.86 (2H, AB system, J = 15.0 Hz),
3.51-3.57 (1H, m), 4.46 (1H, center of m), 5.29 (1H, d, J = 1.8
Acknowledgment. We thank Mr. Walter Sgroi for his
contribution to this work, Dr. Valeria Rocca and Dr. Carlo
Scapolla for performing HPLC analyses, and the University
of Genova, MIUR (PRIN 06 and a Ph.D. grant to V.C.) and
Fondazione S. Paolo for financial assistance.
Supporting Information Available: General experimental
methods, temperature-time profile for the experiments per-
formed in microwave reactor, additional spectroscopic data for
compounds 4, crystallographic data and full-page size ORTEP
of trans-4a, copies of NMR spectra, and X-ray data of trans-4a
(CIF). This material is available free of charge via the Internet at
http://pubs.acs.org.
Hz), 5.37 (1H, d, J = 1.5 Hz), 5.50 (1H, s), 7.09-7.26 (9H, m). 13
C
NMR (DMSO-d6): δ 22.0 (CH2), 35.9 (CH2), 47.4 (CH2), 58.26
(CH3), 58.37 (CH), 69.1 (CH), 69.8 (CH2), 115.5 (CH2), 127.7
(CH), 128.0 (CH), 128.1 (2C, CH), 128.6 (2C, CH), 128.7 (CH),
128.9 (CH), 130.7 (CH), 132.0 (C), 137.3 (C), 138.4 (C), 148.9 (C),
166.8 (C), 169.8 (C).
J. Org. Chem. Vol. 75, No. 15, 2010 5143