Synthesis of azepines by a gold-catalyzed intermolecular [4 + 3]-annulation

Article abstract of DOI:10.1021/ja803890t

A convenient gold(III)-catalyzed synthesis of azepines from the intermolecular annulation of propargyl esters and α,β-unsaturated imines is reported (19 examples, 55-95% yield). This formal [4 + 3]-cycloaddition reaction is proposed to proceed via a stepwise process involving intramolecular trapping of an allyl-gold intermediate. Copyright

Full text of DOI:10.1021/ja803890t

Published on Web 06/25/2008
Synthesis of Azepines by a Gold-Catalyzed Intermolecular [4 + 3]-Annulation
Nathan D. Shapiro and F. Dean Toste*
Department of Chemistry, UniVersity of California, Berkeley, California 94720
Received May 29, 2008; E-mail: fdtoste@berkeley.edu
Table 1. Optimization of the Au-Catalyzed [4 + 3]-Cycloaddition
Gold catalysis has recently generated a variety of valuable methods
for the synthesis of complex structures from simple starting materials.1
While the majority of efforts have focused on intramolecular re-
arrangement and addition reactions, a number transformations taking
advantage of intermolecular reaction of the a gold-stabilized cationic
intermediate generated from the 1,2-rearrangement of propargyl esters
have been described.2 In these reactions, the cationic intermediate
shows reactivity analogous to that reported for electrophilic metal-
stabilized vinylcarbenoids.3–5 For example, we have shown that
sulfoxides react with intermediate A to form carbonyl compounds (eq
1).5 On the basis of this reactivity, we postulated that allylgold
intermediate B, generated by reaction of A with a nucleophile, could
be induced to react with electrophiles. Herein, we report the realization
of this goal leading to a convenient method for the construction of
azepines.
a By 1H NMR versus an internal standard.
Table 2. [4 + 3]-Cycloaddition of R,ꢀ-Unsaturated Imines
In analogy to related reactions of rhodium-stabilized vinylcar-
benoids,6 we reasoned that generation of allylgold intermediate B
and a proximate electrophile could be accomplished by reaction of
A with a nucleophilic diene, such as an R,ꢀ-unsaturated imine. On
the basis of this hypothesis, we were pleased to find that subjecting
propargyl ester 1 and N-phenyl imine 2 to our typical conditions
for cationic triphenylphosphinegold(I)-catalyzed reactions afforded
a trace amount of azepine 3 (Table 1, entry 1). While changing the
ligand from triphenylphosphine to an N-heterocyclic carbene only
slightly improved the yield (entry 2), the use of 5 mol % of AuCl
allowed for the formation of azepine 3 in 44% yield (Table 1, entry
3). On the basis of reports that suggest AuCl may form Au(III)
species in situ,7 we subsequently examined Au(III) sources and
were pleased to find that picolinic acid derived catalyst 4 catalyzed
formation of the desired product with increased efficiency (65%
yield, entry 5).8
With conditions in hand, we examined the scope of the gold-
catalyzed [4 + 3]-cycloaddition (Table 2). In general, the highest
yields were obtained with substrates containing electron-rich N-aryl
groups on the imine nitrogen (entries 1-5). On the other hand, the
reaction proved highly tolerant of variation at the other positions
of the unsaturated imine component. For example, having the olefin
conjugated with electron-rich and electron-deficient aryl groups had
little impact on the yield of the cycloaddition (entries 6 and 7).
The olefin substituents can also be aliphatic. For example, imine 9
underwent chemoselective [4 + 3]-cycloaddition to afford 10 in
60% yield without cyclopropanation of the isolated alkene (entry
9). Additionally, gold-catalyzed cycloaddition of vinyl bromide 11
produced a 63% yield of bromoazepine 12, a potential cross-
coupling partner (entry 10).
a Conditions: 1.3 equiv of 1, 5% 4, CH2Cl2, rt. Ar′
4-HO-2,6-Me2-C6H2.
)
We next turned to examine the scope of the propargyl ester
component of the cycloaddition (Table 3). With secondary benzylic
propargyl esters 13 and 15, the reactions provided azepine products
14 and 16 in good yields and as single diastereomers (entries 1 and
2).9 Tertiary propargyl esters also participated in the cycloaddition
addition, smoothly affording all-carbon quaternary centers in azepines
18 and 20, albeit with diminished diastereocontrol (entries 3 and 4).
Similarly, tert-butylcyclohexanone derived ester 21 underwent the gold-
catalyzed cycloaddition to generate 22 with 2.5:1 dr with respect to
the axial stereocenter (entry 5).
A proposed mechanism that accounts for this diastereoselectivity
is detailed in Scheme 1. Gold-promoted isomerization of the propargyl
9
9244 J. AM. CHEM. SOC. 2008, 130, 9244–9245
10.1021/ja803890t CCC: $40.75
2008 American Chemical Society

C O M M U N I C A T I O N S
Table 3. Diastereoselective Transformations of Propargyl Esters
In conclusion, we have developed a Au(III)-catalyzed synthesis of
azepines via the annulation of simple, readily available starting materials.
This is exemplified by the fact that both components employed in the
cycloaddition reaction to form azepine 30 can be generated from gold-
catalyzed rearrangements of propargyl ester 15 (eq 4). In addition to
representing a rare example of a Au-catalyzed intermolecular annulation
reaction,13 the [4 + 3]-cycloaddition highlights the generation and
subsequent electrophilic trapping of an allyl-gold intermediate from gold-
stablized vinylcarbenoid A. The development of reactions that take
advantage of this mechanistic paradigm is ongoing in our laboratories and
will be reported in due course.
Acknowledgment. We gratefully acknowledge NIHGMS (RO1
GM073932), Merck Research Laboratories, Bristol-Myers Squibb,
Amgen Inc., and Novartis for funding. N.D.S. thanks Eli Lilly for a
graduate fellowship.
Supporting Information Available: Experimental procedures and
compound characterization data. This material is available free of charge
via the Internet at http://pubs.acs.org.
a Conditions: 1.3 equiv of propargyl ester, 5% 4, CH2Cl2, rt.
b Conditions: 2 equiv of propargyl ester, 10% 4, dichloromethane, 60
°C. Ar′ ) 4-HO-2,6-Me2-C6H2.
References
(1) For recent reviews of gold-catalyzed reactions, see: (a) Jime´nez-Nunez,
E.; Echavarren, A. M. Chem. Commun. 2007, 333. (b) Gorin, D. J.; Toste,
F. D. Nature 2007, 446, 395. (c) Furstner, A.; Davies, P. W. Angew. Chem.,
Int. Ed. 2007, 46, 3410. (d) Hashmi, A. S. K. Chem. ReV. 2007, 107, 3180.
(e) Shen, H. C. Tetrahedron 2008, 64, 3885.
Scheme 1. Mechanistic Hypothesis
(2) (a) Marion, N.; Nolan, S. P. Angew. Chem., Int. Ed. 2007, 46, 2750. (b)
Correa, A.; Marion, N.; Fensterbank, L.; Malacria, M.; Nolan, S. P.; Cavallo,
L. Angew. Chem., Int. Ed. 2008, 47, 718.
(3) (a) Miki, K.; Ohe, K.; Uemura, S. J. Org. Chem. 2003, 68, 8505. (b)
Johansson, M. J.; Gorin, D. J.; Staben, S. T.; Toste, F. D. J. Am. Chem.
Soc. 2005, 127, 18002. (c) Gorin, D. J.; Dube, P.; Toste, F. D. J. Am.
Chem. Soc. 2006, 128, 14480. (d) Gorin, D. J.; Watson, I. D. G.; Toste,
F. D. J. Am. Chem. Soc. 2008, 130, 3736.
(4) (a) Amijs, C. H. M.; Lo´pez-Carrillo, V.; Echavarren, A. M. Org. Lett. 2007,
9, 4021. (b) Davies, P. W.; Albrecht, S. J.-C. Chem. Commun. 2008, 238.
(5) Witham, C. A.; Mauleo´n, P.; Shapiro, N. D.; Sherry, B. D.; Toste, F. D.
J. Am. Chem. Soc. 2007, 129, 5838.
(6) (a) Doyle, M. P.; Hu, W.; Timmons, D. J. Org. Lett. 2001, 3, 3741. (b)
Doyle, M. P.; Yan, M.; Hu, W.; Gronenberg, L. S. J. Am. Chem. Soc.
2003, 125, 4692. (c) Davies, H. M. L.; Hu, B.; Saikali, E.; Bruzinski, P. R
J. Org. Chem. 1994, 59, 4535. For a related reaction of Fischer carbenes,
see: (d) Barluenga, J.; Tom´ as, M.; Ballesteros, A.; Santamaria, J.; Carbajo,
R. J.; Lo´pez-Ortiz, F.; Garcia-Granda, S.; Pertierra, P. Chem.sEur. J. 1996,
2, 88. (e) Barluenga, J.; Toma´s, M.; Rubio, E.; Lopez-Pelegrin, J. A.; Garcia-
Granda, S.; Priede, M. P. J. Am. Chem. Soc. 1999, 121, 3065. (f) Barluenga,
J.; Toma´s, M.; Rubio, E.; Lopez-Pelegrin, J. A.; Garcia-Granda, S.; Priede,
M. P. J. Am. Chem. Soc. 1999, 121, 3065.
ester leads to gold-carbenoid intermediate A.10,11 Subsequent nu-
cleophilic addition of the imine nitrogen generates allylgold intermedi-
ate 23 that undergoes intramolecular nucleophilic addition onto the
pendant iminium electrophile via transition state 24.
(7) Lemiere, G.; Gandon, V.; Agenet, N.; Goddard, J. P.; de Kozak, A.; Aubert,
C.; Fensterbank, L.; Malacria, M. Angew. Chem., Int. Ed. 2006, 45, 7596.
(8) (a) Hashmi, A. S. K.; Weyrauch, J. P.; Rudolph, M.; Kurpejovic, E. Angew.
Chem., Int. Ed. 2004, 43, 6545. (b) Hashmi, A. S. K.; Kurpejovic, E.;
Wo¨lfle, M.; Frey, W.; Bats, J. W. AdV. Synth. Catal. 2007, 349, 1743.
(9) The trans-diaryl stereochemistry, which is opposite to that produced in
related rhodium-catalyzed cycloadditions,6a was established by an X-ray
crystal structure (see Supporting Information) of 13.
Additional studies revealed that electron-donating substituents on
the N-aryl and ꢀ-aryl groups enhance the rate of the gold-catalyzed
cycloaddition, supporting a stepwise mechanism in which formation
of iminium 23 is rate-determining.12 On the basis of this observation,
we envisioned that heteroaryl imines might also serve as heterodienes
in the gold-catalyzed [4 + 3]-cycloaddition. We were pleased to find
that indole azepine 26 was formed from the gold-catalyzed cyclo-
addition of 1 with imine 25, albeit at slightly elevated temperatures
and increased catalyst loading (eq 2). On the other hand, quinoline
imine 27 underwent gold-catalyzed coupling with propargyl ester 1 to
furnish tricyclic azepine 28 in 93% yield at room temperature (eq 3).
(10) As in the intermolecular cyclopropanation of these intermediates,3b chirality
was not transferred in the cycloaddition of enantioenriched propargyl ester
15 with imine 2b (see Supporting Information).
(11) The observation that the E/Z-selectivities obtained by trapping with
sulfoxides are not identical to the diastereoselectivity observed in the
cycloaddition suggests that A is formed reversibly2b and reacts with
nucleophile dependent selectively (see Supporting Information).
(12) See Supporting Information for details.
(13) For additional examples of intermolecular gold-catalyzed annulations, see:
(a) Melhado, A. D.; Luparia, M.; Toste, F D. J. Am. Chem. Soc. 2007,
129, 12638. (b) Hsu, Y.-C.; Datta, S.; Ting, C.-M.; Liu, R.-S. Org. Lett.
2008, 10, 521. (c) Zhang, G.; Huang, X.; Li, G.; Zhang, L. J. Am. Chem.
Soc. 2008, 130, 1814. (d) Barluenga, J.; Ferna´ndez-Rodr´ıguez, M. A.;
Garc´ıa-Garc´ıa, P.; Aguilar, E. J. Am. Chem. Soc. 2008, 130, 2764.
JA803890T
9
J. AM. CHEM. SOC. VOL. 130, NO. 29, 2008 9245