Gold-catalyzed [3+3]-annulation of azomethine imines with propargyl esters

Article abstract of DOI:10.1021/ja903863b

(Chemical Equation Presented) The gold-catalyzed [3+3]-cycloaddition reaction of propargyl esters and azomethine imines has been developed. The reaction provides a rapid entry into a wide range of substituted tetrahydropyridazine derivatives from simple s

Full text of DOI:10.1021/ja903863b

Published on Web 07/31/2009
Gold-Catalyzed [3+3]-Annulation of Azomethine Imines with Propargyl Esters
Nathan D. Shapiro, Yun Shi, and F. Dean Toste*
Department of Chemistry, UniVersity of California, Berkeley, California, 94720
Received May 12, 2009; E-mail: dtoste@berkeley.edu
Table 1. Reaction Optimization
The reactions of alkenyl Fischer carbenes 1 with 1,3-dipoles
typically proceed via a concerted-asynchronous [3+2] cycloaddition
(eq 1). Considering the orbitals involved in these transformations,
the isolobal analogy allows the comparison of the reactivity of 1
to that of Lewis acid complexed acrylates.1 In contrast, the LUMO
of alkenyl metal carbenoids of type 2 may be approximated as
singlet vinylcarbenes (eq 2).2,3 Given this analogy, a [3+3]-
cycloaddition between 1,3-dipoles and carbenoids of type 2 would
be predicted. Unfortunately, free electrophilic vinylcarbenes undergo
rapid rearrangement to cyclopropenes, and intermolecular cycload-
ditions of these species are typically low yielding.4,5 This problem
has been circumvented through the use of alkenyl metal-carbenoids
2, which are typically generated in situ from metal-catalyzed diazo
decomposition;6 however, cycloaddition reactions of 1,3-dipoles
with carbenoids7 of type 2 have yet to be reported. We report herein
a gold(III)-catalyzed [3+3]-cycloaddition8 of propargyl esters and
azomethine imines, which is proposed to proceed via stepwise
cycloaddition with a gold(III)-carbenoid intermediate of type 2.9-11
entry
catalyst
solvent temp conversion
yielda
dr (cis:trans)
b
1
2
3
CD2Cl2 rt
MeCN rt
NO2Me rt
100% 90%
(6:1)
(6:1)
(5:1)
(3:1)
(8:1)
(6:1)
(6:1)
-
PicAuCl2 (6)
6
6
c
48%
71%
-
44%
61%
49%
c
d
4
5
6
6
C6D6
rt
c
e
CD2Cl2 0 °C 100%
89% (79% )
100% 73%
100% 85%
6
7
8
9
NaAuCl4
AuCl3
AuBr3
CD2Cl2 rt
CD2Cl2 rt
CD2Cl2 rt
20%
<5%
<5%
<5%
Ph3PAuCl/AgSbF6 CD2Cl2 rt
-
a Yield and diastereomeric ratio determined by 1H NMR versus an
internal standard. b Pic ) 2-picolinate. c Reaction time was 4 h. d The
starting ylide was partially insoluble in 0.3 M C6D6. e Isolated yield of
analytically pure cis 5a.
With optimal conditions in hand (entry 5), the substrate scope
of the gold-catalyzed [3+3]-cycloaddition reaction was exam-
ined. As demonstrated in the reaction of ꢀ-phenyl substituted
azomethine imine 4a, substitution of the ꢀ-position of the
pyrazolidinone generally provides bicyclic product 5a with high
cis selectivity (Vida infra). Alkyl substituents are also tolerated
at this position (Table 2, entries 1-2), with larger substituents
giving increased selectivity (20:1 for tert-butyl versus 8:1 for
methyl). Remarkably, even an alkynyl substituent is sufficient
to provide high selectivity (7:1, entry 3). Moreover, this reaction
was readily extended to the synthesis of tetracycle 7 (eq 3).
Following the initial [3+3] cycloaddition of azomethine imine
4p, the alkyne was deprotected with TBAF and subjected to
Au(I)-catalyzed hydroarylation conditions to deliver 7.16
The azomethine imine can also be substituted at the R-position,
although in this case the product (5e) was formed with 1.3:1 cis:
trans diastereoselectivity (entry 4). On the other hand, the cycload-
dition of azomethine imine 4f, having both R- and ꢀ-substituents,
remained highly selective (10:1, entry 5). Finally, the backbone
need not be substituted (entry 7) but can also accommodate
quaternary carbons in either position (entries 8-9).
Beginning with our previously optimized reaction conditions,9d
we were delighted to find that bicyclic [3+3] cycloadduct 5a was
formed in 90% yield and with 6:1 cis:trans diastereoselectivity in
the Au(III)-catalyzed reaction of ylide 4a with propargyl ester 3a
(Table 1, entry 1).12,13 While varying the solvent failed to provide
an increase in the diastereoselectivity (entries 2-4), lowering the
temperature to 0 °C improved the ratio of cis:trans to 8:1 (entry
5).14 Other Au(III) chloride salts also catalyzed the reaction with
only slightly diminished yields (entries 6-7); however, Au(III)
bromide and various Au(I) catalysts failed to provide any of the
desired product (entries 8-9).15
The aldehyde-derived substituent of the azomethine imine can
also be varied. Both electron-rich and electron-deficient aryl groups
are well tolerated in the gold(III)-catalyzed cycloaddition (entries
10-11). Ortho-substituted aryl groups are also accommodated but
provide the cycloadducts with significantly lower diastereoselec-
tivity (entries 12-13). Finally, the cycloaddition reaction of ylides
derived from aliphatic aldehydes generally proceeded in lower yield
(entry 14).
An additional stereocenter is generated when secondary propargyl
esters are employed (eqs 4, 5). In this case, regardless of whether
the cycloaddition is concerted or stepwise (as depicted),17 the high
1,2-cis diastereoselectivity can be rationalized as resulting from the
9
11654 J. AM. CHEM. SOC. 2009, 131, 11654–11655
10.1021/ja903863b CCC: $40.75  2009 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Azomethine Imine Scope
Supporting Information Available: Experimental procedures,
compound characterization data (PDF), and X-ray structure data (CIF).
This material is available free of charge via the Internet at http://
pubs.acs.org.
References
(1) (a) Barluenga, J.; Rodr´ıgues, F.; Fan˜ana´s, F. J.; Flo´rez, J. Top. Organomet.
Chem. 2004, 13, 59. (b) Barluenga, J.; Santamaría, J.; Toma´s, M. Chem.
ReV. 2004, 104, 2259. (c) Sierra, M. A.; Ferna´ndez, I.; Coss´ıo, F. P. Chem.
Commun. 2008, 4671.
(2) (a) Davies, H. M. L.; Clark, D. M.; Alligood, D. B.; Elband, G. R.
Tetrahedron 1987, 43, 4265. (b) Davies, H. M. L.; Hu, B. Tetrahedron
Lett. 1992, 33, 455.
(3) For descriptions of singlet vinylcarbene, see: (a) Hoffmann, R.; Zeiss, G. D.;
Van Dine, G. W. J. Am. Chem. Soc. 1968, 90, 1485. (b) Davis, J. H.;
Goddard, W. A., III; Bergman, R. G. J. Am. Chem. Soc. 1977, 99, 2427.
(c) Sevin, A.; Arnaud-Danon, L. J. Org. Chem. 1981, 46, 2346. (d)
Yoshimine, M.; Pacansky, J.; Honjou, N. J. Am. Chem. Soc. 1989, 111,
2785.
(4) (a) Bertrand, G. Ed.; Carbene Chemistry: From Fleeting Intermediates to
Powerful Reagents; FontisMedia: Lausanne, Dekker, New York, 2002. (b)
Moss, R. A., Platz, M. S., Jones, M., Jr., Eds.; ReactiVe Intermediate
Chemistry; Wiley-Interscience: Hoboken, NJ, 2004.
(5) Nucleophilic singlet vinylcarbenes react as 3-carbon units in cycloadditions
with olefins; see: Boger, D. L.; Wysocki, R. J., Jr. J. Org. Chem. 1988, 53,
3408.
(6) (a) Davies, H. M. L. Curr. Org. Chem. 1998, 2, 463. (b) Davies, H. M. L.;
Walji, A. M. In Modern Rhodium-Catalyzed Organic Reactions; Evans,
P. A., Ed.; Wiley-VCH: Weinheim, Germany, 2005; p 301.
(7) For the first use of the term carbenoid as a “description of intermediates
which exhibit reactions qualitatively similar to those of carbenes without
necessarily being free divalent carbon species,” see: Closs, G. L.; Moss,
R. A. J. Am. Chem. Soc. 1964, 86, 4042.
(8) For examples of formal [3+3] cycloaddition reactions of azomethine imines,
see: (a) Shintani, R.; Hayashi, T. J. Am. Chem. Soc. 2006, 128, 6330. (b)
Chan, A.; Scheidt, K. A. J. Am. Chem. Soc. 2007, 129, 5334. (c) Perreault,
C.; Goudreau, S. R.; Zimmer, L. E.; Charette, A. B. Org. Lett. 2008, 10,
689.
(9) For examples of gold-catalyzed intermolecular cycloaddition reactions using
propargyl esters, see: (a) Johansson, M. J.; Gorin, D. J.; Staben, S. T.;
Toste, F. D. J. Am. Chem. Soc. 2005, 127, 18002. (b) Gorin, D. J.; Dube´,
P.; Toste, F. D. J. Am. Chem. Soc. 2006, 128, 14480. (c) Gorin, D. J.;
Watson, I. D. G.; Toste, F. D. J. Am. Chem. Soc. 2008, 130, 3736. (d)
Shapiro, N. D.; Toste, F. D. J. Am. Chem. Soc. 2008, 130, 9244.
(10) For additional examples of gold-catalyzed intermolecular cycloaddition
reactions, see: (a) Ito, Y.; Sawamura, M.; Hayashi, T. J. Am. Chem. Soc.
1986, 108, 6405. (b) Asao, N.; Takahashi, K.; Lee, S.; Kasahara, T.;
Yamamoto, Y. J. Am. Chem. Soc. 2002, 124, 12650. (c) Kusama, H.;
Miyashita, Y.; Takaya, J.; Iwasawa, N. Org. Lett. 2006, 8, 289. (d) Melhado,
A. D.; Luparia, M.; Toste, F. D. J. Am. Chem. Soc. 2007, 129, 12638. (e)
Zhang, G.; Huang, X.; Li, G.; Zhang, L. J. Am. Chem. Soc. 2008, 130,
1814. (f) Zhang, G.; Zhang, L. J. Am. Chem. Soc. 2008, 130, 12598.
(11) (a) Fu¨rstner, A.; Davies, P. W. Angew. Chem., Int. Ed. 2007, 46, 3410. (b)
Hashmi, A. S. K. Chem. ReV. 2007, 107, 3180. (c) Gorin, D. J.; Toste,
F. D. Nature 2007, 446, 395. (d) Shen, H. C. Tetrahedron 2008, 64, 7847.
(e) Jime´nez-Nu´n˜ez, E.; Echavarren, A. M. Chem. ReV. 2008, 108, 3326.
(12) The major isomer was assigned to be cis by X-ray crystallography (see
Supporting Information).
a Reaction performed at room temperature. b 2 mmol scale.
cis-imine geometry and the preferred trans geometry of the
proposed gold-carbenoid intermediate.9d,18 To gain further insight
into the origin of the 1,2-cis stereoselectivity, secondary propargyl
ester 8c was reacted with tert-butyl substituted azomethine imine
4c (eq 5).19 In this case, a 2:1 mixture of diastereomers with respect
to the pyrazolidinone substituent, and favoring the 1,3-trans isomer
of 9c, was formed.20 Furthermore, the high diastereoselectivity in
the gold-catalyzed reactions of 3a can be rationalized by minimiza-
tion of unfavorable steric interactions between the propargyl ester
methyl groups and the ꢀ-substituent in the ring closing transition
state (eq 6). These results suggest that the diastereoselectivity is
determined during ring closing, rather than in the formation of
allylgold intermediate 10.13
(13) Similar cis-selectivity has been observed; see: ref 8. (a) Sua´rez, A.; Downey,
C. W.; Fu, G. C. J. Am. Chem. Soc. 2005, 127, 11244. (b) Bonin, M.;
Chauveau, A.; Micouin, L. Synlett 2006, 15, 2349.
(14) Employing a different propargyl ester (acetate or pivolate) provided no
change in selectivity.
(15) HCl, PtCl2, PdCl2(PPh3)2, [IrCl(cod)]2, and [RuCl2(CO)3]2 failed to promote
this reaction.
(16) Nevado, C.; Echavarren, A. M. Chem.sEur. J. 2005, 11, 3155.
(17) Additional evidence for a stepwise mechanism was obtained in the reaction
of azomethine imine 11, which furnished enamine 12 after ring fragmenta-
tion and tautomerization.
In conclusion, we have developed a gold(III)-catalyzed synthesis
of diazabicycles from readily available starting materials.21 This
report represents the first example of a formal cycloaddition between
alkenyl metal carbenoids and 1,3-dipoles. In contrast to the previ-
ously reported cycloadditions,9d,10f this reaction highlights the
difference in the reactivity of alkenyl Fischer carbenes and the
alkenyl Au-carbenoids generated from the rearrangement of pro-
pargyl esters. Further studies exploring and exploiting this difference
are ongoing and will be reported in due course.
(18) Witham, C. A.; Mauleo´n, P.; Shapiro, N. D.; Sherry, B. D.; Toste, F. D.
J. Am. Chem. Soc. 2007, 129, 5838.
(19) This substrate combination was chosen to aid in characterization of the
products. Nearly identical selectivites were observed in reactions employing
either 8a or 8c.
(20) The configuration of the minor isomer was confirmed by X-ray crystal-
lography (see Supporting Information).
(21) For further synthetic transformations of the diazabicycles, see the Supporting
Information.
Acknowledgment. We gratefully acknowledge NIHGMS (RO1
GM073932), Bristol-Myers Squibb, and Novartis for funding and
Johnson Matthey for the generous donation of AuCl3. Y.S. thanks
the China Scholarship Council (Grant No. [2008]3019) for a
predoctoral fellowship.
JA903863B
9
J. AM. CHEM. SOC. VOL. 131, NO. 33, 2009 11655