Formation of spirocyclic compounds from heck cyclizations invoking cyclic enamides

Article abstract of DOI:10.1021/jo800650e

(Chemical Equation Presented) The palladium-mediated transformation of 3,4-dihydro-2(1H)-pyridinones 12 featuring a (2-bromophenyl)ethyl substituent in the 5-position produces spirocyclic products, imides 14 and amides 15. The formation of these products

Full text of DOI:10.1021/jo800650e

Formation of Spirocyclic Compounds from Heck Cyclizations
Invoking Cyclic Enamides
Gedu Satyanarayana and Martin E. Maier*
Institut fu¨r Organische Chemie, UniVersita¨t Tu¨bingen, Auf der Morgenstelle 18, 72076 Tu¨bingen, Germany
martin.e.maier@uni-tuebingen.de
ReceiVed March 25, 2008
The palladium-mediated transformation of 3,4-dihydro-2(1H)-pyridinones 12 featuring a (2-bromophe-
nyl)ethyl substituent in the 5-position produces spirocyclic products, imides 14 and amides 15. The
formation of these products can be explained by insertion of the enamide double bond into the initial
aryl-Pd bond followed by oxidation or reduction of the organopalladium intermediate. Alternatively,
formation of these spiro compounds might proceed via acyliminium ion intermediates.
Introduction
disubstituted alkenes, forcing the initial organopalladium species
to enter into useful domino reactions.5–8
A typical feature of the Heck reaction is the transformation
of an organopalladium species into another one by insertion of
an alkyne or alkene into the initial Pd-C bond.1 In the case of
an alkene, the insertion is followed by elimination of PdHX,
provided that a ꢀ-hydrogen is available for syn-elimination. For
example, Heck reactions on cyclohexene or other cyclic alkenes
with aryl halides lead to 3-arylcyclohexenes (cyclohex-2-en-1-
ylbenzenes) or other double-bond isomers.2 If a ꢀ-hydride
elimination is not possible other intramolecular reactions can
occur. A famous example is the Catellani process3,4 where the
insertion product from norbornene undergoes an intramolecular
C-H insertion leading to a palladacycle that can be used for
further transformations. Furthermore, substrates for intramo-
lecular Heck reactions have been constructed, that contain 1,1-
Commonly, normal alkenes or electron-poor alkenes are used
in the Heck reaction.1 However, even electron-rich alkenes such
as enol ethers and enamides have been employed as well. In
general, enamides undergo Heck coupling with the carbon next
to the nitrogen atom.9 The transformation of the aryl iodide 1
containing an enamide appendage illustrates an intramolecular
example that follows this rule (Figure 1).10,11 Via intermediate
A the spiro compound 2 was formed. The thallium salt additive
prevented migration of the double bond. An unusual case is
the cyclization of enamide 3.12 The alkene insertion should lead
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5410 J. Org. Chem. 2008, 73, 5410–5415
10.1021/jo800650e CCC: $40.75 2008 American Chemical Society
Published on Web 06/17/2008

Pd-Catalyzed Spiro Cyclization of Cyclic Enamides
FIGURE 2. Possible products in the intramolecular Heck reaction of
aryl halides connected to a cyclic enamide via a C-2 tether; X ) halide,
R ) alkyl, aryl.
FIGURE 1. Examples of intramolecular Heck reactions onto cyclic
by Michael addition to ethyl acrylate furnished the formyl esters
11a-f.26 Cyclization to the enamides 12a-f was accomplished
by heating the formyl esters with benzylamine in the presence
of acetic acid.
Using one of the enamides, 1-benzyl-5-[2-(2-bromo-5-meth-
oxyphenyl)ethyl]-3,4-dihydropyridin-2(1H)-one (12d), its pal-
enamides.
to intermediate B, which has no syn ꢀ-hydrogen next to the
Pd-I substituent. Double bond formation to pentacycle 4 can
only be explained by epimerization of the Pd-bearing center,
possibly through the corresponding iminium ion.
As a result of our interest in the synthesis of nitrogen-
containing scaffolds,13,14 we planned to investigate the pal-
ladium-catalyzed transformation of aryl halides of type 5,
containing a cyclic enamide connected via a two carbon tether
(Figure 2). The aryl-palladium intermediate C might attack the
enamide double bond either in a 5-exo- or a 6-endo-mode. The
6-endo-pathway would lead to intermediate D with hydrogen
atoms available for subsequent ꢀ-hydride elimination. This way
the annulated ring system 6 or a double bond isomer thereof
might be formed. The spiro mode seems more likely in terms
of stereoelectronic considerations.15,1 However, this pathway
would generate intermediate E without a C-H vicinal to the
C-PdX bond. Regeneration of the Pd(0) should be possible in
the presence of a hydride source, which would correspond to a
well-known reductive Heck cyclization.16–18 This should result
in spiro amides like 7. While less common then annulated
systems, spirocyclic ring systems can be found in a variety of
natural and unnatural products.19,20
(16) For some recent examples of reductive Heck cyclizations, see: (a) Sole,
D.; Bonjoch, J.; Garcia-Rubio, S.; Peidro, E.; Bosch, J. Chem. Eur. J. 2000, 6,
655–665. (b) Trost, B. M.; Thiel, O. R.; Tsui, H.-C. J. Am. Chem. Soc. 2003,
125, 13155–13164. (c) Banerjee, M.; Mukhopadhyay, R.; Achari, B.; Banerjee,
A. K. J. Org. Chem. 2006, 71, 2787–2796. (d) Liu, P.; Huang, L.; Lu, Y.;
Dilmeghani, M.; Baum, J.; Xiang, T.; Adams, J.; Tasker, A.; Larsen, R.; Faul,
M. M. Tetrahedron Lett. 2007, 48, 2307–2310. (e) Donets, P. A.; Van der Eycken,
E. V. Org. Lett. 2007, 9, 3017–3020. (f) Bower, J. F.; Szeto, P.; Gallagher, T.
Org. Biomol. Chem. 2007, 5, 143–150.
(17) For some examples of bimolecular reductive Heck coupling reactions,
see: (a) Namyslo, J. C.; Kaufmann, D. E. Chem. Ber./Recueil 1997, 130, 1327–
1331. (b) Kasyan, A.; Wagner, C.; Maier, M. E. Tetrahedron 1998, 54, 8047–
8054. (c) Cox, C. D.; Malpass, J. R. Tetrahedron 1999, 55, 11879–11888. (d)
Wei, Z.-L.; George, C.; Kozikowski, A. P. Tetrahedron Lett. 2003, 44, 3847–
3850.
(18) For a review, see: Mitchell, D.; Yu, H. Curr. Opin. Drug DiscoVery
DeV. 2003, 6, 876–883.
(19) For reviews, see: (a) El Bialy, S. A. A.; Braun, H.; Tietze, L. F. Synthesis
2004, 2249–2262. (b) Dake, G. Tetrahedron 2006, 62, 3467–3492.
(20) For some recent papers describing the synthesis of 7-azaspiro[4.5]decane
derivatives, see: (a) Yang, L.; Morriello, G.; Prendergast, K.; Cheng, K.; Jacks,
T.; Chan, W. W. S.; Schleim, K. D.; Smith, R. G.; Patchett, A. A. Bioorg. Med.
Chem. Lett. 1998, 8, 107–112. (b) Bendl, M.; Eder, M.; Langhammer, I.; Urban,
E. Heterocycles 2000, 53, 115–126. (c) Harrison, T. J.; Patrick, B. O.; Dake,
G. R. Org. Lett. 2007, 9, 367–370.
(21) Compound 8b: (a) Bard, R. R.; Bunnett, J. F.; Traber, R. P. J. Org.
Chem. 1979, 44, 4918–4924. (b) van Klink, G. P. M.; de Boer, H. J. R.; Schat,
G.; Akkerman, O. S.; Bickelhaupt, F.; Spek, A. L. Organometallics 2002, 21,
2119–2135.
Results and Discussion
The corresponding substrates of type 5 were easily prepared
from bromoiodobenzenes21–24 8a-f. A Jeffery-Heck coupling25
of these aryl iodides with 3-butenol led to the corresponding
4-(2-bromo)phenyl-butanals 9a-f in reasonable yields ranging
from 65% to 85% (Scheme 1, Table 1). Subsequent enamine
formation using pyrrolidine in the presence of K2CO3 followed
(22) Compound 8c: Vu, C. B.; Corpuz, E. G.; Merry, T. J.; Pradeepan, S. G.;
Bartlett, C.; Bohacek, R. S.; Botfield, M. C.; Eyermann, C. J.; Lynch, B. A.;
MacNeil; I. A; Ram, M. K.; van Schravendijk, M. R.; Violette, S.; Sawyer, T. K.
J. Med. Chem. 1999, 42, 4088–4098.
(23) Compound 8d: (a) Kuwabe, S.-i.; Torraca, K. E.; Buchwald, S. L. J. Am.
Chem. Soc. 2001, 123, 12202–12206. (b) Fu¨rstner, A.; Kennedy, J. W. J. Chem.
Eur. J. 2006, 12, 7398–7410.
(24) Compound 8e, 8f: Orito, K.; Hatakeyama, T.; Takeo, M.; Suginome,
H. Synthesis 1995, 1273–1277.
(13) (a) Khartulyari, A. S.; Maier, M. E. Eur. J. Org. Chem. 2007, 317–324.
(b) Prusov, E.; Maier, M. E. Tetrahedron 2007, 63, 10486–10496.
(14) (a) Satyanarayana, G.; Maier, M. E. Tetrahedron 2008, 64, 356–363.
(b) Satyanarayana, G.; Mu¨ller, S.; Maier, M. E. Tetrahedron Lett. 2008, 49,
3279–3282.
(25) (a) Jeffery, T. Tetrahedron Lett. 1991, 32, 2121–2124. (b) Wolfe, J. P.;
Rennels, R. A.; Buchwald, S. L. Tetrahedron 1996, 52, 7525–7546. (c) Tietze,
L. F.; Kahle, K.; Raschke, T. Chem. Eur. J. 2002, 8, 401–407. (d) Bruye`re, D.;
Bouyssi, D.; Balme, G. Tetrahedron 2004, 60, 4007–4017.
(26) Padwa, A.; Brodney, M. A.; Marino, J. P., Jr; Sheehan, S. M. J. Org.
Chem. 1997, 62, 78–87.
(15) Baldwin, J. E. J. Chem. Soc., Chem. Commun. 1976, 734–741.
J. Org. Chem. Vol. 73, No. 14, 2008 5411

Satyanarayana and Maier
TABLE 2. Reaction of Piperidinone 12d with a Palladium
SCHEME 1. Synthesis of Cyclic Enamides 12a-f via Heck
Coupling, Michael Addition of Enamines 10a-f to Ethyl
Acrylate, and Cyclization of 4-Formyl Esters 11a-f with
Benzylamine
Catalyst, Base, and Ph3P under Different Conditionsa
temp 13d
14d
(%)
15d
(%)
entry
catalyst
ligand solvent
(°C)
(%)
1b
2c
3
4
5
6
7
8
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(PPh3)2Cl2
Pd(PPh3)4
Pd(PPh3)4
PPh3
PPh3
PPh3
PPh3
PPh3
DMF
DMF
DMF
DMF
toluene
DMF
DMF
toluene
120
120
120
100
120
120
120
120
46
40
10
11
15
19
35
7
trace
trace
21
9
24
24
18
45
18
37
33
44
37
37
32
30
TABLE 1. Yields for Transformations Leading to Piperidinones
12a-f
coupling step Michael addition cyclization to enamide
a Typical conditions: Pd(OAc)2 (0.1 equiv), PPh3 (0.2 equiv), Cs2CO3
(4 equiv), aryl bromide 12d (0.16-0.2 M), 72 h. b In the presence of
Et3SiH (1.5 equiv). c In the presence of HCO2Na (1.5 equiv).
R1
R2
(%)
(%)
(%)
H
H
H
OMe
H
9a (85)
9b (72)
9c (65)
9d (71)
9e (76)
9f (71)
11a (74)
11b (71)
11c (67)
11d (72)
11e (74)
11f (72)
12a (85)
12b (82)
12c (69)
12d (84)
12e (75)
12f (80)
Me
CO2Me
H
The 13C NMR DEPT spectrum of imide 14d shows the
expected five methylene groups. The quaternary spiro center
resonates at δ ) 54.2 ppm. The imide carbonyl functions appear
at δ ) 172.2 and 175.8 ppm, respectively. In the spiro amide
15d the quaternary spiro center is shifted to higher field,
resonating at δ ) 45.8 ppm. As compared to 14d the
diastereotopic protons of the NCH2Ph group of amide 15d show
a classical AB-system in the 1H NMR spectrum with two
doublets (δ ) 4.77 and 4.29 ppm) separated by 0.48 ppm.
Similar patterns and features are seen in the NMR spectra of
the other examples (vide infra). An additional AB-system
appears due to the presence of the methylene group at C2′
(δ ) 3.13 and 2.96 ppm).
In a similar manner, the other enamides 12a-f (except for
d) were transformed to the spiro compounds 14a-f and 15a-f,
respectively. In these cases the conditions from entry 4
(Pd(OAc)2, PPh3, DMF, 120 °C, 72 h) and entry 8 (Pd(PPh3)4,
toluene, 120 °C, 72 h) were used. With the latter conditions we
wanted to see whether the preferential formation of the spiro
imides in toluene would be observed with the other substrates
as well. These results are summarized in Table 3.
The formation of these spiro derivatives can be explained by
a Heck cyclization (Scheme 2). Thus, it seemed that the initial
arylpalladium species F inserts the enamide double bond
generating an intermediate of type G. This intermediate might
be converted to either the imide 14 or the amide 15. Alterna-
tively, the iminium ion H might be a possible intermediate en
route to 14 and 15. In this case, instead of a ꢀ-hydride
elimination, the palladium might be expelled by formation of
the iminium ion H. The imide 14 is then formed by oxidation
of the iminium ion H. The amide 15 would be the result of a
reduction of the iminium ion H.
OMe OMe
OMe
H
ladium-catalyzed transformation was studied under various
conditions (Table 2). With regard to the palladium source, base,
and solvent, classical conditions [Pd(OAc)2, PPh3, Cs2CO3,
DMF, 120 °C, 72 h] were employed. Since we expected the
5-exo cyclization mode to be preferred as mentioned above,1,15
we ran the reaction in the presence of a hydride source
(triethylsilane and sodium formate, entries 1 and 2) in order to
release Pd(0) from the putative intermediate E (Figure 2). While
these reactions did indeed produce the spiro amide 15d, its yield
was low or moderate in the case of sodium formate (37%). The
major product turned out to be the debrominated enamide 13d.
Then we wanted to see which products were formed without
an external hydride source (entries 3-8). Analysis of the
reaction mixture by LC-MS indicated three products, one of
them being the debrominated compound 13d. The other two
turned out to be the spiro compounds 14d and 15d. Running
the reaction at lower temperature (100 °C, entry 4) increased
the yield for spiro amide 15d. It seems that higher temperatures
favors the oxidation product, imide 14d. The reaction worked
equally well in toluene as solvent, giving a combined yield of
61% for the two spiro compounds (entry 5). We also examined
other palladium catalysts in place of Pd(OAc)2. Since these
catalysts already contain at least two phosphine ligands, no
additional Ph3P was added (entries 6-8). Experiments 6 and 7,
which were run in DMF at 120 °C, showed Pd(PPh3)2Cl2 to be
better than Pd(PPh3)4, since the latter gave more (35%) of the
debrominated product 13d. In toluene as solvent and Pd(PPh3)4
as catalyst (entry 8), the formation of the debrominated product
13d (7%) could be essentially suppressed in favor of the imide
14d (45%). Considering the total yield of the two spiro
compounds toluene is the ideal solvent, giving a combined yield
of 75%.
Although in general terms the mechanism in Scheme 2 seems
plausible, the source of the oxygen that leads to the imides 14
and the source of the hydride required for reduction of the
5412 J. Org. Chem. Vol. 73, No. 14, 2008

Pd-Catalyzed Spiro Cyclization of Cyclic Enamides
TABLE 3. Palladium-Catalyzed Transformation of 5-(2-Bromophenyl)ethyl-Substituted 3,4-Dihydro-2(1H)-pyridinones 12a-f a
a Reaction conditions: Pd(OAc)2 (0.1 equiv), PPh3 (0.2 equiv), Cs2CO3 (4 equiv), DMF (0.18-0.2 M), 120 °C, 72 h or Pd(PPh3)4 (0.1 equiv), Cs2CO3
(4 equiv), toluene (0.18-0.2 M), 120 °C, 72 h. b Yield in DMF as solvent. c Yield in toluene as solvent.
iminium ion to the amides 15 are not yet clear. An initial
hypothesis was that the hydride comes from the DMF solvent.
This was tested with DMF-D7 on enamide 12a (Scheme 3.)
15b is independent of the palladium source. Entries 2 and 3
show that for the reaction in toluene the catalyst Pd(PPh3)4 gives
a higher overall yield (78%) for the two spiro compounds 14b
and 15b. Changing the base from Cs2CO3 to Hu¨nig’s base (entry
4) shut down the reaction completely. From this experiment
we conclude that Cs2CO3 serves not only as base but possibly
also as an oxygen soure, explaining the formation of the imides
14.
In summary, we could demonstrate the facile synthesis of
spiro compounds 14 and 15 from easily accessible cyclic
enamides 12. These enamides carry a (2-bromophenyl)ethyl
substituent in the 5-position that makes it possible to trigger a
palladium-mediated reaction cascade resulting in spiro-imides
14 and amides 15. The starting materials, the cyclic enamides
12, are easily available from bromoiodobenzenes 8 via a Heck
coupling with butenol with concomitant internal reduction of
the double bond (redox reaction) leading to 4-aryl-butanals 9.
After conversion of the aldehydes 9 to the corresponding
enamines 10, a Michael reaction with ethyl acrylate gave rise
to the formyl esters 11. These could be cyclized with benzyl
amine in the presence of acetic acid to the enamides 12.
1
However, according to LC-MS and the H and 13C NMR
spectra, the spiro compound 15a did not show any incorporation
of a deuterium. The only conclusion that can be drawn from
this result is that the hydride most likely comes from the
phosphine ligand. Furthermore, precursors of the imide 14a
might provide a hydride equivalent. This hydride transfer might
be mediated by Pd as is the case in the formation of aldehydes
9 (Scheme 1).27 In fact, a recent paper also describes some
examples for a reductive Heck cyclization without an added
hydride source.8f
Using enamide 12b, further studies were conducted in order
to delineate the effects of the palladium source and the base or
additive (Table 4.) Entry 1 was run in the presence of sodium
formate and Pd(PPh3)2Cl2 demonstrating that the prefential
formation of the debrominated byproduct 13b and spiro amide
(27) For an example, where iridium functions as a hydride shuttle, see:
Yamaguchi, R.; Kawagoe, S.; Asai, C.; Fujita, K.-i. Org. Lett. 2008, 10, 181–
184, and references therein.
J. Org. Chem. Vol. 73, No. 14, 2008 5413

Satyanarayana and Maier
TABLE 4. Spiro Cyclization of Enamide 12b in the Presence of
Various Additives
SCHEME 2. Proposed Mechanism Explaining Formation of
14 and 15a
a For simplicity phosphine ligands are omitted.
13b 14b 15b
entry
catalyst
base
additive solvent (%) (%) (%)
HCO2Na DMF 45 trace 40
toluene trace 32
SCHEME 3. Spiro Cyclization of Enamide 12a in the
Presence of DMF-D7
1
2
3
4
Pd(PPh3)2Cl2 Cs2CO3
Pd(PPh3)2Cl2 Cs2CO3
Pd(PPh3)4
Pd(PPh3)4
28
32
Cs2CO3
(iPr)2NEt
toluene
toluene
7
46
(3.4 mL) in H2O (13 mL) was added followed by refluxing of the
mixture for 2 h. After cooling to ambient temperature, the mixture
was treated with 3 N HCl, and extracted with ethyl acetate (3 ×
30 mL). The combined organic extracts were washed with saturated
NaCl solution, dried (Na2SO4), and filtered. Concentration of the
filtrate and purification of the crude product by flash chromatog-
raphy (ethyl acetate/hexane, 1:8) furnished the aldehyde ester 11a
(3.2 g, 74% for two steps) as colorless oil. Rf ) 0.4 (ethyl acetate/
hexane, 3:97 to 1:8); 1H NMR (400 MHz, CDCl3) δ [ppm] 9.65 (1
H, s, CHdO), 7.51 (1 H, d, J ) 8.1 Hz, 3′-H), 7.28-7.15 (2 H, m,
Ar-H), 7.06 (1 H, ddd, J ) 9.2, 8.1, 2.3 Hz, Ar-H), 4.12 (2 H,
q, J ) 7.1 Hz, OCH2CH3), 2.86-2.64 (2 H, m, 6-H), 2.50-2.20
(3 H, m), 2.10-1.88 (2 H, m, 2-H), 1.92-1.64 (2 H, m, 3-H), 1.24
(3 H, t, J ) 7.1 Hz, OCH2CH3); 13C NMR (100 MHz, CDCl3) δ
[ppm] 203.8 (CHdO), 172.9 (OCdO), 140.5 (C-1′), 132.9 (C-3′),
130.4 (CH), 128.0 (CH), 127.6 (CH), 124.2 (C-2′), 60.5
(OCH2CH3), 50.6 (C-4), 33.5 (C-6), 31.5 (C-2), 28.8 (C-5), 23.5
(C-3), 14.2 (OCH2CH3).
1-Benzyl-5-[2-(2-bromophenyl)ethyl]-3,4-dihydropyridin-2(1H)-
one (12a). To a magnetically stirred solution of the formyl ester
11a (1.8 g, 5.5 mmol) in CH2ClCH2Cl (10 mL) at room temperature
were added sequentially benzyl amine (1.2 mL, 11 mmol) and
AcOH (0.3 mL, 5.5 mmol) followed by refluxing of the mixture
for 12 h. After cooling, the reaction mixture was treated with
aqueous NaHCO3 solution and extracted with ethyl acetate (3 ×
20 mL). The combined organic layers were washed with brine, dried
(Na2SO4), and filtered. Concentration of the filtrate followed by
flash chromatography (ethyl acetate/hexane, 1:9 to 1:2) furnished
the cyclic enamide 12a (1.7 g, 85%) as brown viscous oil. Rf )
0.45 (ethyl acetate/hexane, 1:2); IR (neat) νmax/cm-1 3062, 3030,
2925, 2838, 1667, 1496, 1439, 1408, 1212, 1026, 957, 751, 703;
1H NMR (400 MHz, CDCl3) δ [ppm] 7.55 (1 H, dd, J ) 7.9, 1.0
Hz, 3′-H), 7.40-7.28 (3 H, m, Ar-H), 7.28-7.18 (3 H, m, Ar-H),
7.16 (1 H, dd, J ) 7.4, 1.8 Hz, 6′-H), 7.08 (1 H, ddd, J ) 9.2, 7.9,
1.8 Hz, 4′-H), 5.79 (1 H, s, 6-H), 4.66 (2 H, s, NCH2Ph), 2.84 (2
H, CH2Ar) and 2.62 (2 H, CH2C-5) [2 t, J ) 7.9 Hz], 2.36 (2 H,
4-H) and 2.34 (2 H, 3-H) [2 t, J ) 8.1 Hz]; 13C NMR (100 MHz,
CDCl3) δ [ppm] 168.8 (NCdO), 140.5 (C-1′), 137.2 (C), 132.8
(C-3′), 130.3 (CH), 128.5 (2 C, CH), 127.7 (CH), 127.4 (3 C, CH),
127.3 (CH), 124.7 (C-6), 124.2 (C-2′), 118.8 (C-5), 48.8 (NCH2Ph),
34.7 (CH2Ar), 34.0 (CH2C-5), 31.2 (C-3), 24.2 (C-4); HRMS (ESI)
calcd for C20H21BrNO [M + H]+ 370.0801, found 370.0801.
Palladium-Catalyzed Spiro Cyclization of 5-(2-Bromophenyl)-
ethyl-Substituted Enamide 12a. To a solution of the bromoenamide
12a (188 mg, 0.51 mmol) in anhydrous DMF (3 mL), in an oven-
dried Schlenk tube fitted with a rubber septum, were added Ph3P
Formation of the spiro compounds 14 and 15 can be explained
by insertion of the enamide double bond into the aryl-Pd bond.
Oxidation of the alkene insertion product on the one hand and
reduction on the other hand leads to the imides 14 and the
amides 15, respectively. Alternatively, the resulting intermediate
might expel Pd(0) and HBr generating an iminium ion.
Preliminary studies show that the hydride required for the
reduction of the putative iminium ion or palladium intermediate
is not coming from the solvent. The fact that carbonate as a
base is essential points to the fact that the oxygen atom in the
imides might originate from the carbonate. Although we could
show the preparative value of the transformation, further studies
are required in order to clarify the exact mechanism. These
transformations are unprecedented and further illustrate the
power of transition metal catalyzed transformations.
Experimental Section
Ethyl 6-(2-Bromophenyl)-4-formylhexanoate (11a). To a
magnetically stirred solution of the aldehyde28 9a (3.0 g, 13.2 mmol)
in C6H6 (12 mL) was added anhydrous K2CO3 (5.47 g, 39.6 mmol)
followed by pyrrolidine (2.2 mL, 26.4 mmol). The reaction mixture
was stirred for 6 h at room temperature. Then the mixture was
treated with saturated aqueous NaHCO3 solution, extracted with
diethyl ether (3 × 30 mL), dried (Na2SO4), filtered, and concentrated
in vacuo to provide the crude enamine 10a. To the crude enamine
in CH3CN (12 mL) at 5 °C was added molecular sieves (4 Å, 2 g)
followed by ethyl acrylate (2.3 mL, 21.1 mmol). The resultant
mixture was stirred for 2 h at room temperature and then refluxed
for 2 h. After cooling of the mixture to room temperature, AcOH
(28) (a) Kuwabe, S.-i.; Torraca, K. E.; Buchwald, S. L. J. Am. Chem. Soc.
2001, 123, 12202–12206. (b) Qadir, M.; Priestley, R. E.; Rising, T. W. D. F.;
Gelbrich, T.; Coles, S. J.; Hursthouse, M. B.; Sheldrake, P. W.; Whittall, N.;
Hii, K. K. Tetrahedron Lett. 2003, 44, 3675–3678.
5414 J. Org. Chem. Vol. 73, No. 14, 2008

Pd-Catalyzed Spiro Cyclization of Cyclic Enamides
(26.6 mg, 20 mol%), Cs2CO3 (662 mg, 2 mmol), and Pd(OAc)2
(11.4 mg, 10 mol%) at room temperature under nitrogen atmo-
sphere. The magnetically stirred reaction mixture was heated in an
oil bath at 120 °C for 3 days. The mixture was cooled to room
temperature and washed with aqueous 3N HCl solution. After
separation of the layers, the aqueous layer was extracted with ethyl
acetate (3 × 10 mL). The combined organic layers were washed
with saturated NaCl solution, dried (Na2SO4), and filtered. Evapora-
tion of the filtrate and purification of the crude material by flash
chromatography (ethyl acetate/hexane, 1:9 to 1:4) furnished as first
fraction the imide 14a (30 mg, 19%) as brown viscous oil. Further
elution of the column using ethyl acetate/hexane (1:4 to 1:3) gave
the debromoenamide 13a (20 mg, 13%) as brown viscous oil.
Continuation of the elution with ethyl acetate/hexane (1:3 to 3:2)
provided the amide 15a (56 mg, 38%) as brown viscous oil.
1-Benzyl-5-(2-phenylethyl)-3,4-dihydropyridin-2(1H)-one (13a).
Rf ) 0.65 (ethyl acetate/hexane, 4:1); IR (neat) νmax/cm-1 3032,
Hz, 5′-H); 13C NMR (100 MHz, CDCl3) δ [ppm] 175.5 (C-2′), 172.1
(C-6′), 144.2 (C-7a), 143.8 (C-3a), 137.4 (C), 128.9 (2 C, CH),
128.4 (2 C, CH), 128.2 (CH), 127.4 (CH), 126.7 (CH), 125.2 (CH),
123.2 (CH), 55.0 (C-(1,3′)), 43.3 (NCH2Ph), 36.4 (C-3), 30.2 (C-
2), 30.1 (C-5′), 28.7 (C-4′); HRMS (ESI) calcd for C20H20NO2 [M
+ H]+ 306.1489, found 306.1487.
1′-Benzyl-2,3-dihydro-6′H-spiro[indene-1,3′-piperidin]-6′-one (15a).
Rf ) 0.4 (ethyl acetate/hexane, 4:1); IR (neat) νmax/cm-1 3064, 3029,
2926, 2852, 1643, 1604, 1488, 1454, 1417, 1358, 1248, 761, 735,
1
702; H NMR (400 MHz, CDCl3) δ [ppm] 7.40-6.90 (9 H, m,
Ar-H), 4.77 (1 H, d) and 4.28 (1 H, d) [J ) 14.5 Hz, NCH2Ph],
3.16 (1 H, d, J ) 12.5 Hz) and 2.97 (1 H, dd, J ) 12.5, 2.0 Hz)
[2′-H], 2.79 (1 H, ddd, J ) 16.3, 8.7, 4.8 Hz), 2.74-2.45 (3 H,
m), 2.14 (1 H, ddd, J ) 13.2, 9.7, 7.4 Hz), 1.94 (1 H, ddd, J )
12.7, 8.1, 4.6 Hz), 1.89-1.75 (1 H, m), 1.76-1.65 (1 H, m); 13C
NMR (100 MHz, CDCl3) δ [ppm] 169.4 (NCdO), 146.7 (C-7a),
143.4 (C-3a), 136.9 (C), 128.5 (2 C, CH), 128.4 (2 C, CH), 127.5
(CH), 127.4 (CH), 126.5 (CH), 124.8 (CH), 122.6 (CH), 55.9 (C-
2′), 50.2 (NCH2Ph), 46.5 (C-(1,3′)), 35.0 (C-3), 31.7 (C-5′), 29.6
(C-2′), 29.5 (C-2); HRMS (ESI) calcd for C20H22NO [M + H]+
292.1696, found 292.1696.
1
2924, 2852, 1667, 1495, 1454, 1409, 1211, 1029, 700; H NMR
(400 MHz, CDCl3) δ [ppm] 7.50-7.10 (10 H, m, Ar-H), 5.79 (1
H, s, 6-H), 4.68 (2 H, s, NCH2Ph), 2.75 (2 H, CH2Ar) and 2.62 (2
H, CH2C-5) [2 t, J ) 7.9 Hz], 2.37 (2 H, 4-H) and 2.35 (2 H, 3-H)
[2 t, J ) 8.4 Hz]; 13C NMR (100 MHz, CDCl3) δ [ppm] 168.8
(NCdO), 141.3 (C-1), 137.3 (C), 128.6 (2 C, CH), 128.3 (4 C,
CH), 127.5 (2 C, CH), 127.3 (CH), 126.0 (CH), 124.6 (C-6), 119.2
(C-5), 48.8 (NCH2Ph), 35.6 (CH2Ar), 34.2 (CH2C-5), 31.2 (C-3),
24.3 (C-4); HRMS (ESI) calcd for C20H22NO [M + H]+ 292.1696,
found 292.1697.
Acknowledgment. Financial support by the Deutsche For-
schungsgemeinschaft and the Fonds der Chemischen Industrie
is gratefully acknowledged. We thank Graeme Nicholson
(Institute of Organic Chemistry) for measuring the HRMS
spectra. G. S. thanks the Alexander von Humboldt foundation
for a postdoctoral fellowship.
1′-Benzyl-2,3-dihydro-2′H,6′H-spiro[indene-1,3′-piperidine]-2′,6′-
dione (14a). Rf ) 0.8 (ethyl acetate/hexane, 4:1); IR (neat) νmax
/
cm-1 3064, 3032, 2925, 2852, 1722, 1674, 1604, 1496, 1477, 1455,
1428, 1376, 1356, 1164, 1079, 1030, 1012, 764, 739, 701; 1H NMR
(400 MHz, CDCl3) δ [ppm] 7.41 (2 H, d, J ) 7.6 Hz, 7-H),
7.36-7.22 (5 H, m, Ar-H), 7.17 (1 H, t, J ) 7.6 Hz, 6-H), 6.98
(1 H, d, J ) 7.6 Hz, 4-H), 5.08 (1 H, d) and 5.03 (1 H, d) [J )
13.7 Hz, NCH2Ph], 3.20-2.95 (2 H, m, 3-H), 2.95-2.65 (3 H,
m), 2.22 (1 H, ddd, J ) 14.0, 8.4, 5.6 Hz, 5′-H), 2.12 (1 H, ddd,
J ) 12.7, 7.6, 5.09 Hz, 4′-H), 2.02 (1 H, ddd, J ) 13.5, 7.1, 5.6
Supporting Information Available: Experimental proce-
dures and characterization for all new compounds reported
and copies of NMR spectra for important intermediates. This
material is available free of charge via the Internet at
http://pubs.acs.org.
JO800650E
J. Org. Chem. Vol. 73, No. 14, 2008 5415