Polyfunctionalized pyrrolidines by Ugi multicomponent reaction followed by palladium-mediated SN2′ cyclizations

Article abstract of DOI:10.1021/jo702087x

(Chemical Equation Presented) A 4-component Ugi reaction with a suitable isocyanide, followed by a novel secondary transformation involving a Pd(II)-mediated (R⁵ = H) or a Pd(0)-mediated (R⁵ = CO ₂Me) S_N2′ cyclization to give highly functionalized N-acyl-2-vinylpyrrolidines, is reported. The overall yields are usually good and in most cases the Pd(0)-catalyzed reaction gave the final product in almost quantitative yield.

Full text of DOI:10.1021/jo702087x

SCHEME 1. Synthesis of Key Isocyanide 4
Polyfunctionalized Pyrrolidines by Ugi
Multicomponent Reaction Followed by
Palladium-Mediated SN2′ Cyclizations
Luca Banfi, Andrea Basso, Valentina Cerulli,
Giuseppe Guanti, and Renata Riva*
UniVersita` di GenoVa, Dipartimento di Chimica e Chimica
Industriale, Via Dodecaneso 31, 16146-GenoVa, Italy
riVa@chimica.unige.it
ReceiVed October 2, 2007
done,5 was therefore submitted to a deprotection-formylation-
dehydration protocol.6
Isocyanide 4 was then used, together with a variety of
carbonyl compounds (usually aldehydes, but also ketones)
(Table 1), primary amines, and carboxylic acids, for preparing
in excellent yield a small library of Ugi derivatives. After
hydrolysis of the carbonate 5a, we attempted to convert the
alcohol 6a into the corresponding allyl bromide, needed for the
previously reported base-mediated cyclization. However, sur-
prisingly, all our efforts to achieve this simple transformation
were unsuccessful.7
For this reason we planned an alternative approach for the
cyclization, taking advantage of the catalytic activity of different
palladium complexes. We first focused our attention on the Pd-
(II) derivatives, which have been used in the past for the
synthesis of N-heterocycles through cyclization of suitable
nitrogen nucleophiles onto allylic alcohols both free and
protected.8-10 The nitrogen nucleophiles were, in those ex-
amples, mostly carbamates or oxazolidinones. To the best of
our knowledge, only one example dealing with amides has been
reported.11
A 4-component Ugi reaction with a suitable isocyanide,
followed by a novel secondary transformation involving a
Pd(II)-mediated (R5 ) H) or a Pd(0)-mediated (R5
)
CO2Me) SN2′ cyclization to give highly functionalized
N-acyl-2-vinylpyrrolidines, is reported. The overall yields
are usually good and in most cases the Pd(0)-catalyzed
reaction gave the final product in almost quantitative yield.
The pyrrolidine ring is an important moiety present in many
natural products and is often included in bicyclic scaffolds and
peptide mimetics.1 Therefore the possibility to obtain highly
and differentially functionalized derivatives in a convergent way
is an important tool in diversity oriented synthesis.2
We recently optimized a very simple method for the prepara-
tion of N-acyl-2-vinylpyrrolidines using a base-promoted cy-
clization (LiHMDS) of an acetamide onto an allylic bromide
through an SN2′ reaction.3 We now decided to extend the same
protocol to more functionalized secondary amides, accessible
in a multicomponent way through the isocyanide-based4 Ugi
reaction. For this purpose we first synthesized the special
isocyanide 4, one of the four inputs in the Ugi MCR, as
summarized in Scheme 1. The alcohol 1, readily obtained in
excellent overall yield by a known procedure from 2-pyrroli-
We therefore started with alcohol 6a, choosing first
PdCl2(PhCN)2 as catalyst. After a careful optimization (reaction
conditions and use of additives, as reported in the Supporting
Information) we found the best conditions which are reported
(5) Hara, O.; Sugimoto, K.; Makino, K.; Hamada, Y. Synlett 2004, 1625-
1627.
(6) The formamide formation step was crucial and only the reported
conditions were successful.
(7) Every attempt to employ different leaving groups failed too.
(8) (a) Hirai, Y.; Terada, T.; Amemiya, Y.; Momose, T. Tetrahedron
Lett. 1992, 33, 7893-7894. (b) Hirai, Y.; Watanabe, J.; Nozaki, T.;
Yokoyama, H.; Yamaguchi, S. J. Org. Chem. 1997, 62, 776-777. (c) Hirai,
Y.; Shibuya, K.; Fukuda, Y.; Yokoyama, H.; Yamaguchi, S. Chem. Lett.
1997, 221-222. (d) Yokoyama, H.; Otaya, K.; Yamaguchi, S.; Hirai, Y.
Tetrahedron Lett. 1998, 39, 5971-5974. (e) Yokoyama, H.; Otaya, K.;
Kobayashi, H.; Miyazawa, M.; Yamaguchi, S.; Hirai, Y. Org. Lett. 2000,
2, 2427-2429. (f) Lei, A.; Liu, G.; Lu, X. J. Org. Chem. 2002, 67, 974-
980. (g) Makabe, H.; Kong, L. K.; Hirota, M. Org. Lett. 2003, 5, 27-29.
(h) Eustache, J.; Van de Weghe, P.; Le Nouen, D.; Uyehara, H.; Kabuto,
C.; Yamamoto, Y. J. Org. Chem. 2005, 70, 4043-4053.
(9) Hirai, Y.; Nagatsu, M. Chem. Lett. 1994, 21-22.
(1) Hanessian, S.; McNaughton-Smith, G.; Lombart, H.-G.; Lubell, W.
D. Tetrahedron 1997, 53, 12789-12854.
(2) Burke, M. D.; Schreiber, S. L. Angew. Chem., Int. Ed. 2004, 43,
46-58.
(3) Banfi, L.; Basso, A.; Guanti, G.; Riva, R. Tetrahedron 2006, 62,
4331-4341.
(4) (a) Do¨mling, A.; Ugi, I. Angew. Chem., Int. Ed. 2000, 39, 3168-
3210. (b) Zhu, J.; Bienayme´, H. Multicomponent Reactions; Wiley:
Weinheim, Germany, 2005. (c) Do¨mling, A. Chem. ReV. 2006, 106, 17-
89. (d) Concerning only the related Passerini reaction see: Banfi, L.; Riva,
R. Org. React. 2005, 65, 1-140.
(10) Yokota, W.; Shindo, M.; Shishido, K. Heterocycles 2001, 54, 871-
885.
(11) Harrington, P. J.; Hegedus, L. S.; McDaniel, K. F. J. Am. Chem.
Soc. 1987, 109, 4335-4338.
10.1021/jo702087x CCC: $40.75 © 2008 American Chemical Society
Published on Web 01/15/2008
1608
J. Org. Chem. 2008, 73, 1608-1611

TABLE 1. Ugi Reaction with Isocyanide 4 and Removal of Carbonate
isolated yield
5 (R5 ) CO2Me)a,b
entry
R1
R2
R3
R4
6 (R5 ) H)
1c
2
3
CH2Ph
Ph
CH2Ph
CH2Ph
n-Bu
n-Bu
n-Bu
CH2Ph
Ph
Ph
H
H
H
H
H
H
H
H
Me
Et
Et
Et
5a: 100
5b: 73 (80)
5c: 94
5d: 86
5e: 99
5f: 79 (92)
5g: 88
5h: 100
6a: 100
6b: 98
6c: 92
6d: 85
6e: 94
6f: 99
4d
5d
6d
7d
8c
i-Pr
i-Pr
t-Bu
o-(OMe)-C6H4
Me
CH2NHBoc
Ph
Ph
CH2CH2CH2Ph
Et
6g: 85
6h: 100
a Based on the isocyanide. b The yield based on recovered 4 is given in parentheses. c Imine was preformed. d The reaction was run in the presence of 4
Å molecular sieves.
TABLE 2. SN2′ Reaction Promoted by Pd(II)
SCHEME 2. Proposed Mechanism for the Pd(II)
Cyclization
substrate
entry (product)
catalysta,b
time (h) yield (%)c
drd
e
1
2
3
4
5
6
7
8
9
6a (7a)
6a (7a)
6a (7a)
6a (7a)
6b (7b)
6c (7c)
6d (7d)
6e (7e)
6f (7f)
PdCl2
118
24
30.6
2.2
3
5.5
6.2
20.3
5.7
3.2
20
47 (68)
65 (67)
71 (80)
77 (89)
75
67 (80)
36 (45)
27 (37)
40 (52)
58
35:65h
37:63h
29:71h
35:65h
29:71h
f
PdCl2(PhCN)2
PdCl2(MeCN)f
PdCl2(MeCN)2
PdCl2(MeCN)2
PdCl2(MeCN)2
PdCl2(MeCN)2
PdCl2(MeCN)2
PdCl2(MeCN)2
PdCl2(MeCN)2
PdCl2(MeCN)2
g
g
g
g
g
g
g
e
73:27i
38:62h
62:38h
87:13i
10
11
6g (7g)
6h (7h)
abutane 10, as previously reported,12 cannot be excluded. The
possible elimination of palladium hydride does not occur.
In that case Pd(II) would be converted into Pd(0) at the end
of the cycle and so the addition of a cooxidant to the reaction
would be necessary; moreover the structure of the products
would be an aldehyde and not a terminal alkene.
a 30% with respect to 5. b All reactions were run in the presence of 4 Å
molecular sieves in THF (entries 2-11) or MeCN (entry 1). c The yield
based on recovered starting material is given in parentheses. d Diastereoi-
somer with minor tR was reported first. e Room temperature (71 h, entry 1;
5 h, entry 11), then reflux (47 h, entry 1; 15 h, entry 11). f Room
temperature. g Reflux. h By GC-MS. i By HPLC.
At least 30% catalyst was necessary for an appreciable rate
and this seems consistent with a rapid pre-equilibrium during
the cyclization, followed by a slow â-elimination.
in entry 2, Table 2. Then we explored different catalysts. The
cheaper PdCl2 gave unsatisfactory results (entry 1), while the
more expensive PdCl2(MeCN)2 (entries 3 and 4) was shown to
be the best. Actually, on 6a this catalyst afforded 7a in slightly
better yield (see entries 2 and 3) and the reaction time and yield
were even improved when the cyclization was run at reflux,
instead of rt (entry 4). In all cases, however, the diastereomeric
ratio was only poor.
Even if detailed studies on the mechanism of this reaction
have not been reported, a possible catalytic cycle, based upon
experimental findings, is reported in Scheme 2. After an
activating complexation of the alkene 6 with Pd(II), a completely
regioselective addition of the nucleophile takes place to give 9.
The transformation into the final product is ensured by a
â-elimination step from the â-hydroxy organopalladium inter-
mediate 9, affording a palladium hydroxide that can enter again
the catalytic cycle after a suitable ligand exchange. Also an
alternative syn elimination from the intermediate palladaox-
Also a certain passivating effect on the catalyst was observed
and this may be responsible for the usually incomplete
transformation of the substrate 6 into 7. Addition of a stoichio-
metric oxidant (p-benzoquinone) or working under air instead
of argon atmosphere led to inferior yields. Moreover, when the
Pd(II) was employed in a stoichiometric amount, an improve-
ment of the rate, but not of the yield, was observed, in accord
with a catalytic reaction with a low turnover number.
We then studied the scope of the reaction on other Ugi
adducts. With the exception of derivatives 6b,c (entries 5 and
6), in all other cases the yields were only moderate, but in one
case a remarkable diastereoselection was observed (entry 10).13
On the contrary alcohol 6h, coming from an Ugi reaction
employing acetone as carbonyl input, did not afford the desired
(12) Hacksell, U.; Daves, G. D, Jr. Organometallics 1983, 2, 772-775.
J. Org. Chem, Vol. 73, No. 4, 2008 1609

cyclizations,8,10,15,16 the inducing stereocenter was always located
in the incoming heterocyclic ring, contrary to our present case.
Also in this case, while the reaction on Ugi products coming
from aldehydes gave excellent results in the Pd(0)-mediated
cyclization, the same strategy applied to 5h did not work. This
time the outcome of the reaction was different with respect to
the Pd(II)-mediated cyclization. Actually, 5h slowly reacted to
give only a terminal conjugated diene (30-40% isolated yield,
as a E/Z mixture referred to the internal double bond), arising
from the formal elimination of HOCO2Me. Most likely the
cyclization of 5h was prevented by steric reasons and so a
competitive reaction occurred.
TABLE 3. SN2′ Reaction Promoted by Pd(0)
substrate
(product)
overall yield
from 4 (%)
entrya
time (h)
yield (%)b
drc
1
2
3
4
5
6
7
8
5a (7a)
5b (7b)
5c (7c)
5d (7d)
5e (7e)
5f (7f)
2
3.3
1.8
3
3
2
100
100
86
92
80 (85)
86
100
73
81
79
79
68
88
54:46d
46:54d
25:75e
89:11d
87:13d
58:42e
5g (7g)
5h (7h)
3
17.5
100
In this note we have reported the first example of an Ugi
reaction followed by an intramolecular SN2′ cyclization, leading
to a series of densely functionalized N-heterocycles. This
protocol represents a further example of how secondary
transformations can expand the scope of isocyanide-based
multicomponent reactions. In this case the isocyanide derived
secondary amide has been transformed into a tertiary one,
converting at the same time the classical acyclic Ugi scaffold
into a heterocyclic one.
Although compounds 7 could be in principle prepared by
acylation of vinyl pyrrolidine with R-aminoacid derivatives
followed by further acylation with synthetic equivalents of R4-
CO2H, this alternative approach would be undoubtly longer and
less convergent. Moreover it would be limited to easily
accessible N-alkylated R-aminoacid derivatives. On the contrary,
our procedure gives access, in a very short (2 steps), convergent,
and high-yielding manner, to compounds 7 with the introduction
of three diversity inputs R1, R2, and R4, including also R2 groups
different from the ones typical of natural R-aminoacids.
The possible preparation of a family of isocyanide analogues
to 4 will allow the introduction of a fourth diversity input,
concerning either the substituents on the pyrrolidine or the ring
size. The presence of stereogenic centers on the isocyanide may
also be helpful for a better control of the stereoselectivity of
the cyclization step.
a All reactions were run in the presence of 10% Pd(PPh3)4, 2 equiv (with
respect to Pd(0)) of diphenyphosphinoethane (dppe), in MeCN at 60 °C.
b The yield based on recovered starting material is given in parentheses.
c Diastereoisomer with minor tR was reported first. d By GC-MS. e By
HPLC.
7h. We experienced a slow reacting rate and initially a new
product, most likely 7h, was observed in TLC. However, it did
not increase with time and, upon bringing the reaction to
completion, it disappeared completely, probably because of an
hydrolytic cleavage of the pyrrolidine-CO bond. The resulting
2-vinylpyrrolidine and 2-(N-benzylpropionamido)-2-methylpro-
panoic acid have indeed been isolated.
This protocol, although well-suited for some secondary
amides, was shown to be dramatically affected by the nature of
groups R1-R4, thus limiting its scope. So we turned our
attention to a different strategy. Although Pd(0)-catalyzed
reactions are a well-known method for the intermolecular
formation of N-C bonds exploiting an allylic carbonate,14 there
are, to the best of our knowledge, only very few examples of
the intramolecular version involving amidic nitrogens as nu-
cleophiles. One of them uses a highly functionalized R-ketoa-
mide15 as nucleophile and a carbonate as leaving group, whereas
two other examples employ an oxazolidinone as nucleophile
and a chloride as leaving group, in the absence10 or in the
presence16 of an alkaline hydride, used to enhance the nucleo-
philicity of the N atom.
For our reaction, tested on carbonate 5a, we used Pd(PPh3)4
in the presence of dppe, working in acetonitrile at 60 °C (Table
3). This time we experienced a complete, fast, and very clean
reaction, isolating 7a in quantitative yield (entry 1).17 The same
protocol on 5b-g gave the expected products 7b-g with
excellent, and in some cases even quantitative, yield. In all
examples employing branched aliphatic aldehydes as carbonyl
inputs in the Ugi condensation, we observed a moderate to good
stereoselectivity (entries 4-6), while aromatic aldehydes gave
poor stereoselection (entries 1, 2, and 8). It should be noted
that in previously reported highly stereoselective Pd-catalyzed
Finally the mildness of the Pd(0) conditions will probably
allow the easy introduction, on R1, R2, or R4 groups, of further
additional functionalities that, in combination with the vinyl
moiety, could be exploited for the synthesis of bicyclic systems.
Our results in this field will be reported in due course.
Experimental Section
General Procedure for the Ugi Reaction. A solution of
isocyanide 4 (0.5-2 mmol) in dry EtOH/CF3CH2OH 1:1 (≈0.4 M
solution) was treated with activated 4 Å powdered molecular sieves
(25 mg/mmol of aldehyde) (entries 2 and 4-7, Table 1). Then
aldehyde (1.5 equiv) and amine (1.65 equiv) (entries 2-7) or
preformed imine (1.5 equiv) (entries 1 and 8) and carboxylic acid
(1.2 equiv) were added. The reaction was stirred at 45 °C until
complete (2-3 h). After filtration of the sieves (when required),
the mixture was diluted with AcOEt and the organic layer was
washed with saturated aq NaHCO3 solution, dried, and concentrated
in vacuo. The crude was purified by chromatography with the
appropriate PE/AcOEt mixture.
(13) Diastereoisomers of 7 have been separated and independently fully
characterized in some cases (7a,b,g). Diastereoisomers of 7d,e,f could not
be separated and therefore they have been characterized as a mixture,
although an accurate determination of the diastereomeric ratio was always
possible (see the Supporting Information).
Compound 5a: pale yellow oil, 100% yield. Rf 0.42 (PE/AcOEt
3:7, UV, molibdic reagent). Anal. found C 69.15, H 7.20, N 6.25;
C26H32N2O5 requires C 69.01, H 7.13, N 6.19. IR νmax 3431, 3000,
1744, 1641, 1447, 1270, 1067, 971, 940. GC-MS tR 13.71; m/z
395 (M+ - 57, 1.5), 291 (23), 280 (10), 252 (19), 215 (9.8), 197
(16), 196 (100), 162 (21), 118 (9.5), 106 (22), 98 (5.6), 92 (8.3),
(14) See, for example: Zumpe, F. L.; Kazmaier, U. Synthesis 1999,
1785-1791 and references therein.
(15) Bulusu, M. A. R. C.; Waldsta¨tten, P.; Tricotet, T.; Rochais, C.; Steck,
A.; Bacher, M. Tetrahedron Lett. 2004, 45, 5833-5836.
(16) Takao, K.; Nigawara, Y.; Nishino, E.; Takagi, I.; Maeda, K.; Tadano,
K.; Ogawa, S. Tetrahedron 1994, 50, 5681-5704.
(17) Working at a lower temperature required a noticeably longer reaction
time and furnished 7a with less satisfactory yield and no improvement with
respect to the diastereomeric ratio.
1
91 (90), 65 (5.4), 57 (8.1). H NMR (CDCl3) δ 1.10 (3H, t, J )
7.4 Hz), 1.57 (2H,
1610 J. Org. Chem., Vol. 73, No. 4, 2008

center of m), 2.04 (2H, q, J ) 7.0 Hz), 2.18-2.46 (2H, m), 3.25
(2H, center of m), 3.77 (3H, s), 4.52 (2H, d, J ) 6.3 Hz), 4.55 and
4.73 (2H, AB system, JAB ) 19.0 Hz), 5.50-5.79 (2H, m), 5.90
(2H, two overlapped s), 6.99-7.35 (10H). 13C NMR (CDCl3) δ
9.2 (CH3), 27.1 (CH2), 28.3 (CH2), 29.5 (CH2), 39.0 (CH2), 49.8
(CH2), 54.6 (CH3), 62.7 (CH), 68.3 (CH2), 123.9, 125.9, 126.7,
128.2, 128.4, 128.6, 129.6, 135.8 (12C, CH), 135.1 (C), 137.6 (C),
155.5 (C), 169.8 (C), 175.6 (C).
General Procedure for Pd(II)-Promoted Cyclization (entries
3-11, Table 2). A solution of PdCl2(MeCN)2 (30% with respect
to 6) in dry THF (2 mL) was treated with activated 4 Å powdered
molecular sieves (40% weight with respect to 6) and the suspension
was carefully degassed and kept under Ar. The alcohol 6 (200-
300 µmol), dissolved in dry THF (6 mL), was added and the
reaction was stirred at rt (entry 3) or refluxed (entries 4-11) for
the appropriate time. The sieves were filtered and the reaction was
diluted with water and extracted with AcOEt. After drying and
solvent removal the crude was purified by chromatography with
10.5 Hz), 5.08 (1H, d, J ) 17.1 Hz), 5.77 (1H, ddd, J ) 17.1,
10.2, 5.7 Hz), 6.34 [1H, br s; at rt 2 clearly prevailing signals in
56:44 ratio at 6.38 (s) and 6.51 (s), respectively], 6.99-7.28 (10H,
m). 13C NMR (DMSO-d6) δ 9.16 (m) and 9.24 (M) (CH3), 20.9
(M) and 22.7 (m) (CH2), 26.0 (M) and 26.4 (m) (CH2), 29.6 (m)
and 31.6 (M) (CH2), 45.6 (m) and 45.8 (M) (CH2), 47.6 (M) and
48.1 (m) (CH2), 57.0 (M) and 60.2 (m) (CH), 58.4 (m) and 59.0
(M) (CH), 113.9 (m) and 114.7 (M) (CH2), 125.3, 125.6, 126.2,
126.4, 126.6, 126.8, 127.2, 127.8, 128.0, 128.16, 128.23, 128.4,
129.5, 129.9 (10C, CH), 133.7, 136.3 and 138.2 (2C, C), 137.3
(m) and 138.8 (M) (CH), 167.87 (M) and 167.93 (m) (C), 174.4
(m) and 174.6 (M) (C). 7aS: white solid. Mp 80.1-82.5 °C. Rf
0.31 (PE/AcOEt 1:9, UV, molibdic reagent). At rt 64:36 mixture
of two highly prevailing rotamers (13C NMR); at 120 °C one
rotamer, but almost all very broad signals (1H NMR). IR νmax 3430,
3018, 2967, 1632, 1411, 1072, 1048, 790. GC-MS tR 14.30; 319
(M+ - 57, 1.8), 252 (8.9), 216 (7.2), 215 (49), 214 (7.8), 197 (13),
196 (77), 124 (8.1), 118 (8.1), 106 (5.2), 92 (7.9), 91 (100), 90
(6.0), 81 (8.2), 65 (7.4), 57 (10). 1H NMR (DMSO-d6, temperature
) 120 °C): δ 1.01 (3H, t, J ) 7.4 Hz), 1.65-1.92 (4H, m), 2.19
(1H, center of m), 2.34 (1H, center of m), 3.07-3.38 (1H, m), 3.60
(1H, center of m), 4.48-4.78 (3H, m), 4.97-5.07 (2H, m), 5.76-
5.90 (1H, m), 6.28 (1H, br s), 6.92-7.26 (10H, m). 13C NMR
(DMSO-d6) (only the signals of the two highly prevailing rotamers
are reported): δ 9.2 (CH3), 20.9 (m) and 23.0 (M) (CH2), 26.3
(M) and 26.5 (m) (CH2), 29.4 (M) and 32.0 (m) (CH2), 45.8 (M)
and 46.2 (m) (CH2), 47.9 (M) and 48.4 (m) (CH2), 57.9 (M) and
60.3 (m) (CH), 58.2 (m) and 59.6 (M) (CH), 113.6 (M) and 115.4
(m) (CH2), 125.5, 126.1, 126.2, 127.8, 127.9, 128.18, 128.25, 128.4,
128.7, 128.9, 129.6, 129.9 (10C, CH), 134.1 (m) and 134.2 (M)
(C), 137.4 (m) and 137.8 (M) (CH), 138.6 (M) and 138.8 (m) (C),
168.0 (M) and 168.6 (m) (C), 174.3 (M) and 174.4 (m) (C).
the
appropriate
PE/AcOEt
mixture
to
give 7.
General Procedure for Pd(PPh3)4-Promoted Cyclization. A
solution of carbonate 5 (150-200 µmol) in dry MeCN (5 mL) was
carefully degassed and kept under Ar. Then dppe (20% with respect
to 5) and Pd(PPh3)4 (10%) were added and the reaction was stirred
at 60 °C until complete. The solution was diluted with water and
extracted with AcOEt. After drying and solvent removal the crude
was purified by chromatography with the appropriate PE/AcOEt
mixture to give 7.
Compound 7a: 77% (89% on recovered starting material) [Pd-
(II)] and 100% [Pd(0)] yield. Anal. found C 76.25, H 7.45, N 7.45;
C24H28N2O2 requires C 76.56, H 7.50, N 7.44. Dr (see Table 2 for
values) by GC-MS [differences with respect to the usual method
(see the Supporting Information: final temperature ) 230 °C, final
time ) 7 min, then to 290 °C in 40 deg/min and final time ) 0);
tR 13.99 (7aF ) faster running in TLC) and 14.30 (7aS ) slower
running in TLC) min]. 7aF: pale yellow oil. Rf 0.45 (PE/AcOEt
1:9, UV, molibdic reagent). At rt: 56:44 mixture of rotamers (CHPh
signal in 1H NMR; M ) major, m ) minor); at 120 °C one rotamer,
but most signals are very broad. IR νmax 3417, 3060, 1635, 1410,
1169, 1075, 717. GC-MS tR 13.99; m/z 319 (M+ - 57, 0.91), 252
(7.3), 216 (7.3), 215 (49), 214 (8.3), 197 (11), 196 (70), 124 (8.1),
118 (8.7), 106 (5.4), 98 (5.2), 96 (5.6), 92 (8.6), 91 (100), 90 (6.6),
81 (7.7), 65 (8.0), 57 (10), 41 (5.2). 1H NMR (DMSO-d6,
temperature ) 120 °C) δ 1.02 (3H, t, J ) 7.5 Hz), 1.66-1.91 (4H,
m), 2.20-2.38 (2H, m), 3.11 (1H, apparent br d, J ) 6.0 Hz), 3.47
(1H, br s), 4.67 (3H, apparent asymmetric s), 4.99 (1H, d, J )
Acknowledgment. The authors gratefully acknowledge Prof.
Lutz Tietze for helpful advice, Mr. Andrea Galatini, Dr. Valeria
Rocca, and Dr. Carlo Scapolla for HPLC analysis, and MUR,
University of Genova (PRIN06) and Fondazione S. Paolo for
financial support.
Supporting Information Available: Full experimental proce-
dures (including additional data for the Pd(II)-catalyzed protocol)
and characterization data for all compounds not already described
(compounds 1-4, 5b-h, 6a-h, 7b-g). This material is available
free of charge via the Internet at http://pubs.acs.org.
JO702087X
J. Org. Chem, Vol. 73, No. 4, 2008 1611