Stereoselective spirolactam synthesis via palladium catalyzed arylative allene carbocyclization cascades

Article abstract of DOI:10.1021/ol101425y

A diastereoselective arylative carbocyclization of pro-nucleophile-linked allenes with aryl and heteroaryl halides to provide spirocyclic lactam products with moderate to high diastereoselectivities and good yields under Pd(0) catalysis is reported. Being operationally simple and tolerant of multiple points of diversity, this complexity building reaction cascade, in which two new carbon-carbon bonds and one new heterocyclic ring are created, should be of high value in both complex natural product synthesis as well as compound library synthesis.

Full text of DOI:10.1021/ol101425y

ORGANIC
LETTERS
2010
Vol. 12, No. 17
3784-3787
Stereoselective Spirolactam Synthesis
via Palladium Catalyzed Arylative Allene
Carbocyclization Cascades
Meiling Li and Darren J. Dixon*
Department of Chemistry, Chemistry Research Laboratory, UniVersity of Oxford,
Mansfield Road, Oxford, OX1 3TA, United Kingdom
Darren.Dixon@chem.ox.ac.uk
Received June 21, 2010
ABSTRACT
A diastereoselective arylative carbocyclization of pro-nucleophile-linked allenes with aryl and heteroaryl halides to provide spirocyclic lactam
products with moderate to high diastereoselectivities and good yields under Pd(0) catalysis is reported. Being operationally simple and tolerant
of multiple points of diversity, this complexity building reaction cascade, in which two new carbon-carbon bonds and one new heterocyclic
ring are created, should be of high value in both complex natural product synthesis as well as compound library synthesis.
The aza-spirocyclic motif is found in many biologically
active natural compounds ranging from the structurally
Scheme 1. Concept and Context of the Palladium(0) Catalyzed
simple to the architecturally complex, including Manzamine
A,1 which exhibits a broad range of interesting biological
properties. Highly innovative and increasingly efficient ways
of accessing these structures have been developed over the
past decade. In this vein, we wished to extend our research
in the field of transition metal catalyzed carbocyclizations
of alkynes2 to appropriately substituted allenes to provide
direct access to arylated spirolactam products of high
synthetic value (Scheme 1).
Allene Carbocyclization Cascade with Aryl Halides
Allenes are a reactive class of compounds able to undergo
a diverse range of chemical transformations (most notably
under palladium catalysis), making them useful starting
materials and intermediates for organic synthesis.3 Hydro-
functionalization of allene under heating (275 °C) was
(1) For a review of the isolation of this and related compounds, see: (a)
Magnier, E.; Langlois, Y. Tetrahedron 1998, 54, 6201. For syntheses, see:
(b) Winkler, J. D.; Axten, J. M. J. Am. Chem. Soc. 1998, 120, 6425. (c)
Martin, S. F.; Humphrey, J. M.; Ali, A.; Hillier, M. C. J. Am. Chem. Soc.
1999, 121, 866. (d) Humphrey, J. M.; Liao, Y.; Ali, A.; Rein, T.; Wong,
Y.-L.; Chen, H.-J.; Courtney, A. K.; Martin, S. F. J. Am. Chem. Soc. 2002,
124, 8584. (e) Toma, T.; Kita, Y.; Fukuyama, T. J. Am. Chem. Soc. 2010,
132, 10233.
(3) For reviews, see: (a) Zimmer, R.; Dinesh, C. U.; Nandanan, E.; Khan,
F. A. Chem. ReV. 2000, 100, 3067. (b) Bates, R. W.; Satcharoen, V. Chem.
Soc. ReV. 2002, 31, 12. (c) Krause, N.; Hashmi, A. S. K. Modern Allene
Chemistry; WILEY-VCH Verlag GmbH & Co.: Weinheim, 2004. (d) Ma,
S. Chem. ReV. 2005, 105, 2829.
(2) Yang, T.; Ferrali, A.; Sladojevich, F.; Campbell, L.; Dixon, D. J.
J. Am. Chem. Soc. 2009, 131, 9140.
(4) Bertrand, M.; Cavallin, B.; Roumestant, M.-L.; Sylvestre-Panthet,
P. Isr. J. Chem. 1985, 26, 95.
10.1021/ol101425y  2010 American Chemical Society
Published on Web 08/10/2010

reported by Bertrand.4 Recently, the transition metal-
catalyzed hydrofunctionalization of allenes with carbon and
heteroatom nucleophiles has been investigated. For example,
Pd(II), Ag(I), Au(III) and Cu(I) complexes can catalyze the
hydrofunctionalization of allenes with C-,5 N-,6 O-7 and S-8
nucleophiles. Relevant to this work, the groups of Ma9 and
Oh10 have reported the regioselective Pd(0)-catalyzed cou-
pling cyclization reaction of 2-(2′,3′-allenyl)malonates with
organic halides leading to either cyclopropyl or cyclopentene
derivatives. Furthermore Pd-catalyzed coupling reactions of
allenic carboxylic acids,11 or allenols,12 or amino allenes13
or carbon nucleophiles14 with organic halides can lead to
the production of arylated heterocyclic motifs. As part of an
ongoing program of research targeting polycyclic alkaloid
natural products, we were interested in the possibility of
developing an efficient and diastereoselective palladium-
catalyzed arylative carbocyclization of allene-tethered pro-
nucleophiles with organic halides. Such a reaction, with its
many points of diversity, would be useful in library genera-
tion and natural product synthesis alike. Herein we report
our findings.
high diastereoselectivities and in moderate to good yields
(Table 1, entries 8-10). However, use of NaOtBu resulted
in the decomposition of the starting material (Table 1, entry
11). Thus it was established that Pd2(dba)3 (5 mol %), dppe
(10 mol %), iodobenzene (1.5 equiv) and K2CO3 (2.0 equiv)
in DMSO at 70 °C were the optimal reaction conditions
(Table 1, entry 9).
With optimal conditions established for 1a, the scope of
the diastereoselective arylative allene carbocyclization cas-
cade with respect to the (hetero)aromatic halide and the
N-substituent of 1 was investigated. Electron-rich and
electron-deficient (hetero)aromatic iodides were investigated,
as were 1-bromonaphthalene, 2-bromonaphthalene and 2-bro-
mopyridine (Table 2). With 1a, reaction yields were good
to excellent and selectivities ranged from 13:1 to 22:1 (Table
2, entries 1-6). Variation to the spectator nitrogen substituent
was not only tolerated but in general led to notable
improvements in the reaction diastereoselectivity; when
N-benzyl substrate was reacted with various aryl and
heteroaryl halides, the observed diastereoselectivities ranged
from 25:1 to 47:1 (Table 2, entries 7-10). Altogether 5
different N-substituents and 12 different (hetero)aryl halides
(iodides and bromides) were successfully employed in the
reaction.
Allene-linked ketoamide 1a was selected for our prelimi-
nary cyclization studies. A coarse screen of Pd(0) catalysts,
ligands, bases and solvents in the presence of 1.5 equiv of
iodobenzene was rapidly met with some success; spirolactam
2a was isolated in 31% yield from a 3:2 mixture of product
diastereomers (56% combined yield) when Pd2(dba)3 (5 mol
%), dppe (10 mol %) and K2CO3 (2.0 equiv) in tetrahydro-
furan at 70 °C (sealed vial) were employed (Table 1, entry
Additionally, extension of this cyclization methodology
to homologous and structurally modified allene-linked pro-
nucleophilic substrates was also achieved and provided
access to a range of spirocyclic scaffolds. Following the
optimized procedure, either iodobenzene or methyl 4-io-
(5) (a) Yamamoto, Y.; Radhakrishnan, U. Chem. Soc. ReV. 1999, 28,
199. (b) Trost, B. M.; Gerusz, V. J. J. Am. Chem. Soc. 1995, 117, 5156. (c)
Besson, L.; Gore, J.; Cazes, B. Tetrahedron Lett. 1995, 36, 3853. (d)
Watanabe, T.; Oishi, S.; Fujii, N.; Ohno, H. Org. Lett. 2007, 9, 4821.
(6) (a) Zhang, Z.; Liu, C.; Kinder, R. E.; Han, X.; Qian, H.; Widenhoefer,
R. A. J. Am. Chem. Soc. 2006, 128, 9066. (b) Lee, P. H.; Kim, H.; Lee, K.;
Kim, M.; Noh, K.; Kim, H.; Seomoon, D. Angew. Chem., Int. Ed. 2005,
44, 1840. (c) Ohno, H.; Toda, A.; Miwa, Y.; Taga, T.; Osawa, E.; Yamaoka,
Y.; Fujin, N.; Ibuka, T. J. Org. Chem. 1999, 64, 2992. (d) Dieter, R. K.;
Yu, H. Org. Lett. 2001, 3, 3855. (e) Morita, N.; Krause, N. Org. Lett. 2004,
6, 4121. (f) Prasad, J. S.; Liebeskind, L. S. Tetrahedron Lett. 1988, 29,
4253.
Table 1. Optimization Studies on Test Substrate 1a
entry solvent
base
time/h convn/%b yield/%c drd
1
2
3
4
5
6
7
8
THF
DCE
DME
CH3OH K2CO3
TBME K2CO3
CH3CN K2CO3
DMF
DMF
DMSO K2CO3
K2CO3
K2CO3
K2CO3
24
48
20
16
50
20
19
16
16
17
17
100
100
100
31
33
33
-
32
60
58
32
58
50
-
3:2
3:2
6:5
-
3:2
10:1
14:1
9:1
17:1
15:1
-
(7) (a) Ma, S.; Yu, Z.; Wu, S. Tetrahedron 2001, 57, 1585. (b)
Hoffmann-Roder, A.; Krause, N. Org. Lett. 2001, 3, 2537. (c) Young, J.-j.;
Jung, L.-j.; Cheng, K.-m. Tetrahedron Lett. 2000, 41, 3411. (d) Marshall,
J. A.; Wang, X.-J. J. Org. Chem. 1991, 56, 4913. (e) VanBrunt, M. P.;
Standaert, R. F. Org. Lett. 2000, 2, 705. (f) Lepage, O.; Kattnig, E.; Furstner,
A. J. Am. Chem. Soc. 2004, 126, 15970. (g) Hashmi, A. S. K.; Schwarz,
L.; Choi, J.-H.; Frost, T. M. Angew. Chem., Int. Ed. 2000, 39, 2285. (h)
Sromek, A. W.; Rubina, M.; Gevorgyan, V. J. Am. Chem. Soc. 2005, 127,
10500.
a
-
100
100
100
100
100
100
K2CO3
Cs2CO3
(8) Morita, N.; Krause, N. Angew. Chem., Int. Ed. 2006, 45, 1897.
(9) (a) Ma, S.; Zhao, S. Org. Lett. 2000, 2, 2495. (b) Ma, S.; Jiao, N.;
Yang, Q.; Zheng, Z. J. Org. Chem. 2004, 69, 6463. (c) Ma, S.; Jiao, N.;
Zhao, S.; Hou, H. J. Org. Chem. 2002, 67, 2837.
9
10
11
DMSO
DMSO
K3PO4
NaOtBu
a
-
(10) Oh, C. H.; Rhim, C. Y.; Song, C. H.; Ryu, J. H. Chem. Lett. 2002,
1140.
a Decomposed. b From crude 1H NMR; c Isolated yields of major
d
1
diastereomer; dr determined from crude H NMR before separation.
(11) Ma, S.; Shi, Z. J. Org. Chem. 1998, 63, 6387.
(12) Ma, S.; Zhao, S. J. Am. Chem. Soc. 1999, 121, 7943.
(13) (a) Ma, S.; Yu, F.; Li, J.; Gao, W. Chem.sEur. J. 2007, 13, 247.
(b) Ma, S.; Gao, W. Org. Lett. 2002, 4, 2989. (c) Shu, W.; Yang, Q.; Jia,
G.; Ma, S. Tetrahedron 2008, 64, 11159. (d) Ma, S.; Jiao, N.; Zheng, Z.;
Ma, Z.; Lu, Z.; Ye, L.; Deng, Y.; Chen, G. Org. Lett. 2004, 6, 2193. (e)
Larock, R. C.; Zenner, J. M. J. Org. Chem. 1995, 60, 482. (f) Larock, R. C.;
Zenner, J. M. J. Org. Chem. 1999, 64, 7312. (g) Cheng, X.; Ma, S. Angew.
Chem., Int. Ed. 2008, 47, 4581. (h) Grigg, R.; Kilner, C.; Mariani, E.;
Sridharan, V. Synlett 2006, 18, 3021.
1). Further studies showed that the reaction diastereoselec-
tivity was dependent on the solvent polarity and could be
improved to 17:1 using DMSO (Table 1, entries 1-3, 5-9).
When methanol was employed as solvent, only substrate
decomposition was witnessed (Table 1, entry 4). A screen
of typical inorganic bases showed that K2CO3, Cs2CO3 and
K3PO4 were all productive, affording the desired product with
(14) (a) Ma, S.; Zheng, Z.; Jiang, X. Org. Lett. 2007, 9, 529. (b) Ma, S.
Acc. Chem. Res. 2003, 36, 701. (c) Hiroi, K.; Kato, F.; Yamagata, A. Chem.
Lett. 1998, 397. (d) Kato, F.; Hiroi, K. Chem. Phar. Bull. 2004, 52, 95.
Org. Lett., Vol. 12, No. 17, 2010
3785

Table 2. Scope of the Palladium(0) Catalyzed Arylative Carbocyclization Cascade with Aromatic and Heteroaromatic Halides
entry
R
1
ArX
time/h
2
yield/%a
drb
1
2
3
4
5
6
7
8
Me
Me
Me
Me
Me
Me
Bn
Bn
Bn
Bn
Pr
a
a
a
a
a
a
b
b
b
b
c
p-MeOC6H4I
3,5-MeC6H3I
p-MeO2C7H4I
m-MeO2C7H4I
2-bromonaphthalene 16
p-BrC6H4I
p-N(CH3)2C6H4I
2-iodothiophene
m-NO2C6H4I
p-MeO2C7H4I
12
12
10
10
b
c
d
e
f
g
h
i
j
k
l
m
n
o
p
79
66
83
86
61
61
50
77
74
67
65
70
66
75
53
18:1
15:1
22:1
13:1
15:1
15:1
33:1
25:1
30:1
47:1
16:1
19:1
30:1
36:1
12:1
45
20
16
12
16
9
10
11
12
13
14
15
1-bromonaphthalene 24
Pr
Allyl
Et
c
p-MeO2C7H4I
p-MeO2C7H4I
p-MeO2C7H4I
2-bromopyridine
10
14
12
20
g
d
d
Et
a Isolated yield of single major diastereoisomer. b dr in crude product.
dobenzoate was employed as the haloarene and the results
are shown in Figure 1. In the formation of spiropiperidin-
2-ones, good reactivity was observed with substrates
possessing six-, seven- and eight-membered ring cyclic
ketones (for 5-membered rings see Table 2) and diaste-
reoselectivities ranged from 7:1 to 22:1 (Figure 1, 3c-3e).
Spiropyrrolidin-2-one products were also accessible in
good to excellent yield albeit with moderate diastereose-
lectivity (Figure 1, 3a, 3b, 3n). A single example of
attempted spiroazapan-2-one production was met with
partial success; product 3f was isolated in 30% yield and
14:1 dr. A range of differentially N-substituted γ- and
δ-lactam derived allene-linked pro-nucleophilic substrates
underwent cyclization with methyl 4-iodobenzoate to give
spiropiperidin-2-one products in moderate to good yields
and good to excellent diastereoselectivity (Figure 1,
3g-3k). Similarly N-protected succinimide or glutarimide
substrates had good reactivity and afforded spiropyrroli-
din-2-one and spiropiperidin-2-one products in good yield
and with moderate to good diastereoselectivities (Figure
1, 3l-3n).
The relative stereochemistries of all the major diastereo-
meric products of 2 and 3 were assigned by analogy to that
of 3i, which was determined by single crystal X-ray
diffraction15 (Figure 1).
(15) X-ray Data were collected at low temperature [Cosier, J.; Glazer,
A. M. J. Appl. Crystallogr. 1986, 19, 105–107] using an Enraf-Nonius
KCCD diffractometer [ Otwinowski, Z.; Minor, W. Processing of X-ray
Diffraction Data Collected in Oscillation Mode Methods Enzymol; Carter,
C. W., Sweet, R. M., Eds.; Academic Press: New York, 1997; p 276]. The
crystal structure of 3i was solved using SIR92 [Altomare, A.; Cascarano,
G.; Giacovazzo, C.; Guagliardi, A.; Burla, M. C.; Polidori, G.; Camalli.,
M. J. Appl. Crystallogr. 1994, 27, 435] and refined using the CRYSTALS
software suite [ Betteridge, P. W.; Carruthers, J. R.; Cooper, R. I.; Prout,
K.; Watkin, D. J. J. Appl. Crystallogr. 2003, 36, 1487] as per the Supporting
Information (CIF file). Crystallographic data (excluding structure factors)
for 3i have been deposited with the Cambridge Crystallographic Data Centre
(CCDC 784231), and copies of these data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif.
Figure 1. Scope of the arylative allene carbocyclization cascade.
aInseparable. bdr in crude product.
3786
Org. Lett., Vol. 12, No. 17, 2010

In conclusion, we have developed a mild, efficient, and
diastereoselective cyclization methodology for the synthesis
of a range of stereodefined arylated spirolactam compounds.
Altogether 15 different spirocyclic structures have been
accessed using this new methodology. Being operationally
simple and tolerating multiple points of diversity, this
reaction should be of use in complex natural product
synthesis as well as compound library synthesis. Work to
expand and apply these findings is ongoing and the results
will be reported in due course.
Acknowledgment. We acknowledge the University of
Oxford and Universities U.K. for an ORS Award (to M.L.)
and Andrew Kyle for X-ray structure determination and the
Oxford Chemical Crystallography Service for the use of the
instrumentation.
Supporting Information Available: Experimental pro-
cedures and spectral data for compounds 1-3. This material
is available free of charge via the Internet at http://pubs.acs.org.
OL101425Y
Org. Lett., Vol. 12, No. 17, 2010
3787