Silver(I)-catalyzed dual activation of propargylic alcohol and aziridine/azetidine: Triggering ring-opening and endo-selective ring-closing in a cascade

Article abstract of DOI:10.1021/jo901877f

(Chemical Equation Presented) [Ag(COD)₂]PF₆ catalyzes the reaction between propargyl alcohols and N-tosylaziridines/azetidines leading to a diverse range of N,O-heterocycles, namely, oxazines, oxazepines, and oxazocines via ring-open

Full text of DOI:10.1021/jo901877f

pubs.acs.org/joc
synchronization of the above events.3 A major ongoing
Silver(I)-Catalyzed Dual Activation of Propargylic
Alcohol and Aziridine/Azetidine: Triggering Ring-
Opening and Endo-Selective Ring-Closing in a
Cascade
program in our laboratory is in late transition metal cata-
lysis, where the goal is to realize differential binding, dual-
activation, and coupling between a π-system and a substrate
having a hard-donor center.4 During the course of our
studies we were attracted by the potential of coinage metals
in general, and silver(I) in particular, to bind/activate
π-systems such as an arene, alkene, or an alkyne on one
hand and substrates bearing a heteroatom such as N, O, and
S on the other.5,6 These features make the coinage metals
trustworthy candidates in facilitating three important reac-
tions, namely (i) the opening of a heterocyclic ring by an
internal/external nucleophile, (ii) the nucleophilic addition
across an alkene/alkyne by an external nucleophile, and
(iii) internal nucleophilic attack across an alkene/alkyne
leading to a ring closure (Figure 1).7-9
Milan Bera† and Sujit Roy*,†,‡
†Organometallics & Catalysis Laboratory, Chemistry
Department, Indian Institute of Technology, Kharagpur
721302, India, and ‡Organometallics & Catalysis Laboratory,
School of Basic Sciences, Indian Institute of Technology,
Bhubaneswar 751013, India
royiitkgp@gmail.com, sroychem@iitbbs.ac.in
Received August 31, 2009
FIGURE 1. Coinage metal (M) assisted binding and ring-opening
events.
(4) (a) Choudhury, J.; Podder, S.; Roy, S. J. Am. Chem. Soc. 2005, 127,
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J. Mol. Catal. A: Chem. 2008, 279, 37.
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G. L.; Kuroda-Sowa, T.; Maekawa, M.; Suenaga, Y.; Maeno, N. J. Am.
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Williams, D. J. Organometallics 2000, 19, 5209. (b) Letinois, U. H.; Weibel,
J. M.; Pale, P. Chem. Soc. Rev. 2007, 36, 759.
[Ag(COD)2]PF6 catalyzes the reaction between propargyl
alcohols and N-tosylaziridines/azetidines leading to a di-
verse range of N,O-heterocycles, namely, oxazines, oxaze-
pines, and oxazocines via ring-opening and ring-closing in
a cascade
(6) Recent reviews on coinage metal catalysis: (a) Patil, N. T.; Yamamato,
Y. Chem. Rev. 2008, 108, 3395. (b) Weibel, J. M.; Blanc, A.; Pale, P. Chem. Rev.
2008, 108, 3149. (c) Corral, M. A.; Dorado, M. M.; Garcia, I. R. Chem. Rev.
2008, 108, 3174.
In recent years tandem catalysis has attracted widespread
attention from synthetic chemists who aim at constructing
complex molecular architecture from simple building
blocks.1 Tandem catalysis involving a transition metal is
often distinguished by (i) selective binding of multiple sub-
strates across the active site(s), (ii) making and breaking of
multiple bonds in a cascade, and (iii) the presence of more
than one distinct catalytic event.2 Therefore the success in
tandem catalysis is interalia dependent on the degree of
(7) Selected examples of heterocycle ring opening by a nucleophile:
(a) Sun, X.; Sun, Y.; Fan, R.; Wu, J. Adv. Synth. Catal. 2007, 349, 2151.
(b) Wang, J. Y.; Hu, Y.; Wang, D. X.; Pan, J.; Huang, Z. T.; Wang, M. X.
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alkyne/alkene: (a) Hashmi, A. S. K.; Grundl, L Tetrahedron 2005, 61, 6231.
(b) Donoghue, P. J.; Kieken, E.; Helquist, P.; Weist, O. Adv. Synth. Catal.
2007, 349, 2647. (c) Sun, J.; Kozmin, S. A. Angew. Chem., Int. Ed. 2006, 45,
4991. (d) Lingaiah, N.; Babu, N. S.; Reddy, K. M.; Sai Prasad, P. S.;
Suryanarayana, I. Chem. Commun. 2007, 278. (e) Luo, Y.; Li, Z.; Li, C. J.
Org. Lett. 2005, 7, 2675. (f) Wang, M. Z.; Wong, M. K.; Che, C. M. Chem.;
Eur. J. 2008, 14, 8353. (g) Tang, J. M.; Liu, T. A.; Liu, R. S. J. Org. Chem.
2008, 73, 8479. (h) Tarselli, M. A.; Liu, A.; Gagne, M. R. Tetrahedron 2009,
65, 1785.
(9) Selected examples of internal nucleophilic attack to alkene/alkyne:
(a) Verniest, G.; Padwa, A. Org. Lett. 2008, 10, 4379. (b) Patil, N. T.; Pahadi,
N. K.; Yamamoto, Y. J. Org. Chem. 2005, 70, 10096. (c) Yang, C. G.; Reich,
N. W.; Chi, Z.; He, C. Org. Lett. 2005, 7, 4553. (d) Yamada, W.; Sugawara,
Y.; Cheng, H. M.; Ikeno, T.; Yamada, T. Eur. J. Org. Chem. 2007, 2604.
(e) Niu, Y. N.; Yan, Z. Y.; Gao, G. L.; Wang, H. L.; Shu, X. Z.; Ji, K. G.;
Liang, Y. M. J. Org. Chem. 2009, 74, 2893. (f) Lee, Y. T.; Chung, Y. K.
J. Org. Chem. 2008, 73, 4698. (g) Yu, M.; Skouta, R.; Zhou, L.; Jiang, H. F.;
Yao, X.; Li, C. J. J. Org. Chem. 2009, 74, 3378.
(1) (a) Wasilke, J. C.; Obrey, S. J.; Baker, R. T.; Banzan, G. C. Chem. Rev.
2005, 105, 1001. (b) Titze, L. F. Chem. Rev. 1996, 96, 115. (c) Ikeda, S. I. Acc.
Chem. Res. 2000, 33, 511.
(2) Fogg, D. E.; Dos Santos, E. N. Coord. Chem. Rev. 2004, 248, 2365.
(3) A few noteworthy examples include Buchwald-Hartwig amination:
(a) Loones, K. T. J.; Maes, B. E. W.; Dommisse, R. A.; Lemiere, G. L. F.
Chem. Commun. 2004, 2466. (b) Bonnaterre, F.; Choussy, M. B.; Zhu, J. Org.
Lett. 2006, 8, 4351. (c) Fang, Y. Q.; Lautens, M. Org. Lett. 2005, 7, 3549.
(d) bryan, C. S.; Lautens, M. Org. Lett. 2008, 10, 4633. Tandem
Heck-Suzuki: Cheung, W. S.; Patch, R. J.; Player, M. R. J. Org. Chem.
2005, 70, 3741. Tandem Heck reaction: Fields, W. H.; Khan, A. K.; Sabat,
M.; Chruma, J. J. Org. Lett. 2008, 10, 5131. Tandem Ugi reaction: Ilyan, A.;
Kysil, V.; Krasavin, M.; Kurashvili, I.; Ivachtchenko, A. V. J. Org. Chem.
2006, 71, 9544.
8814 J. Org. Chem. 2009, 74, 8814–8817
Published on Web 10/15/2009
DOI: 10.1021/jo901877f
r
2009 American Chemical Society

Bera and Roy
JOCNote
Note that, when stitched in a 2-in-1 or 3-in-1 cascade, the above
three reactions can potentially generate myriad opportunities in
multicomponent synthesis.10 Keeping the above in view, we
searched the literature on Ag(I)-catalysis where such cascade
reactions ultimately resulted in a heterocycle. However, such
examples are few.11 Continuing on our success in propargylic
activation12 and aziridine ring-opening13 we are delighted to present
here a Ag(I)-catalyzed tandem ring-opening and ring-closing
involving propargylic alcohol and aziridine or azetidine resulting
in the formation of 6-, 7-, and 8-membered N,O-heterocycles,
namely oxazines, oxazepines, and oxazocines.14 The reaction is
characterized by two main catalytic events operating in a cascade. In
the first event the aziridine or azetidine ring is opened via nucleo-
philic attack by propargylic alcohol. In the second event the tethered
N-nucleophile in the intermediate attacks the alkynic/allenic appen-
dage leading to 100% endoselective ring-closing (Scheme 1).
TABLE 1. [Ag(COD)2]PF6 Catalyzed Ring-Opening/Ring-Closing of
Aziridines and Azetidines with Propargyl Alcohola
SCHEME 1
The model reaction between cyclohexyl-N-tosylaziridine 1a and
propargyl alcohol 2a in the presence of [Ag(COD)2]PF6 (2mol%)
in dichloroethane proceeded well at ambient temperature. At the
consumption of 1a, Cs2CO3 (1 equiv) was added and the reaction
was continued at 80 °C leading to the formation of 1,4-oxazepine
derivative 3 in 72% isolated yield (Scheme 2, Table 1).
SCHEME 2
(10) Selected examples of related multicomponent reactions: (a) Garner,
P.; Kaniskan, H. U.; Hu, J.; Youngs, W. J.; Panzner, M. Org. Lett. 2006, 8,
3647. (b) Cui, S. L.; Wang, J.; Wang, Y. G. Org. Lett. 2007, 9, 5023. (c) Kim,
J. T.; Gevorgyan, V. Org. Lett. 2002, 4, 4697. (d) Yan, B.; Liu, Y. Org. Lett.
2007, 9, 4323. (e) Cui, S. L.; Lin, X. F.; Wang, Y. G. Org. Lett. 2006, 8, 4517.
(f) Lin, C. C.; Teng, T. M; Odedra, A.; Liu, R. S. J. Am. Chem. Soc. 2007, 129,
3798. (g) Xu, X.; Cheng, D.; Li, J.; Guo, H.; Yan, J. Org. Lett. 2007, 9, 1585.
(11) Afewrecentexamples: (a)Binder, J.T.;Kirsch, S.F.Org.Lett. 2006, 8,
2151. (b) Godet, T.; Vaxelaire, C.; Michel, C.; Milet, A.; Belmont, P. Chem.;
Eur. J. 2007, 13, 5632. (c) Su, S.; Porco, J. A., Jr. J. Am. Chem. Soc. 2007, 129,
7744. (d) Bobeck, D. R.;Warner, D. L.; Vedejs, E. J. Org. Chem. 2007, 72, 8506.
(e) Chen, Z.; Yang, X.; Wu, J. Chem. Commun. 2009, 3469.
(f) Blanc, A.; Tenbrink, K.; Weibel, J. M.; Pale, P. J. Org. Chem. 2009, 74, 4360.
(12) (a) Kundu, A.; Prabhakar, S.; Vairamani, M.; Roy, S. Organome-
tallics 1999, 18, 2782. (b) Kundu, A.; Roy, S. Organometallics 2000, 19, 105.
(c) Banerjee, M.; Roy, S. Chem. Commun. 2003, 534. (d) Banerjee, M.; Roy,
S. Org. Lett. 2004, 6, 2137.
aConditions: N-tosylaziridine (0.5 mmol), propargyl alcohol (0.5 mmol),
and[Ag(COD)2]PF6 (2 mol %), dry dichloroethane (2 mL) Cs2CO3 (1equiv).
bIsolated yield.
(13) Bera, M.; Roy, S. Tetrahedron Lett. 2007, 48, 7144.
(14) Oxazine, oxazepine, and oxazocine cores are present in many im-
portant biological molecules. Selected examples: (a) Smits, R. A.; Lim, H.
D.; Stegink, B.; Bakker, R. A.; De Esch, I. J. P.; Leurs, R. J. Med. Chem.
2006, 49, 4512. (b) Kourounakis, A. P.; Charitos, C.; Rekka, E. A.;
Kourounakis, P. N. J. Med. Chem. 2008, 51, 5861. (c) Audouze, K.; Nielsen,
E. O.; Peters, D. J. Med. Chem. 2004, 47, 3089. (d) Novelli, A.; Trelles, R. D.;
Groppetti, A.; Sanchez, T. M. F. Amino Acids 2005, 28, 183.
Control studies (Scheme 3 and Supporting Information
Scheme S1 and Table S1)15 indicated that (i) the optimum
catalyst loading is 2 mol %; (ii) the reaction proceeds with
AgPF6, AgSbF6, and AgBF4 as the catalyst albeit with poorer
yield of the product; (iii) other silver salts such as AgNO3,
J. Org. Chem. Vol. 74, No. 22, 2009 8815

Bera and Roy
JOCNote
SCHEME 3
As discussed later, the formation of oxazepines and oxazines
above is the outcome of the ring-closing step. Gratifyingly, we
could also employ N-tosylazetidines in the present cascade
coupling reaction to provide the corresponding 1,5-oxazocine
derivatives 14-16 in moderate yields (entries 12-14).
While mechanistic details must await further studies, a
proposal on the reaction course is presented in Scheme 4. The
initial event will involve activation of the heteroatoms of the
substrates by [Ag(COD)]þ.17 This will facilitate the opening
of the aziridine/azetidine ring. π-Activation and metallotro-
pic rearrangement of 17 is expected to result in the formation
of intermediates Ag(I)-alkyne 17a, and Ag(I)-allene 17b.
When assisted by a base, the ring-closing event from 17a and
17b may follow endo-dig (path a, path c) or exo-dig/trig (path
b, path d) pathways;subsequent protodemetalation would
afford the organic product and regenerate the Ag(I) catalyst.
It is point worthy that ring-closure via path a involving
7-endo-dig or 8-endo-dig mode and path c involving 6-endo-
dig mode are favored by Baldwin’s rule. Indeed the observed
formation of 1,4-oxazepines, 1,5-oxazocines, and 1,4-oxa-
zines in our hand conforms to the above selection rules. Path
b involving ring-closure in a 6-exo-dig manner is disfavored.
Although the 5-exo-trig mode (path d) for the plausible
formation of oxazolidine 25 is favored, we could not observe
its formation.
Ag2CO3, Ag2SO4, and AgCl do not promote any reaction;
(iv) the product of the first catalytic event, namely 4-methyl-
N-(2-propargyloxycyclohexyl)benzene sulfonamide 30, was
isolated in 80% yield simply by quenching the reaction
after 1 h; (v) the dual combination of [Ag(COD)2]PF6 and
Cs2CO3 efficiently promoted the ring-closing of 30 to 3; and
(vi) Cs2CO3 alone cannot promote the formation 3 and 30
(Scheme 3). All of the above observations highlight the
unique role of Ag(I) in this novel cascade reaction.
It is worth mentioning here that while this work was
nearing completion, two reports on coupling between aryl-
propargyl alcohols and aziridines have appeared. However,
we would like to emphasize that in sharp contrast to our
results, (a) stoichiometric t-BuOK promoted coupling gave
rise to exclusive formation of endocyclic morpholines,16a
while (b) catalytic Yb(OTf)3 promoted coupling yielded
exclusively indene derivatives.16b
The cascade coupling has been satisfactorily extended to
various propargyl alcohols, and substituted N-tosyl azir-
idines/azetidines leading to the selective formation of a
diverse range of N,O-heterocycles, namely 1,4-oxazepines,
1,5-oxazocines, and 1,4-oxazines (Scheme 2, Table 1).
N-Tosylaziridines having an alkyl or aryl appendage
smoothly reacted with propargyl alcohols with terminal
acetylenic linker to provide the corresponding 1,4-oxaze-
pines 3-10 as the exclusive product (entries 1-8). Note
that oxazepine 6 is obtained as a cis-trans mixture (1:1)
possibly due to the conformational equilibrium of the
fused 5- to 7-member bicyclic ring system (entry 4). Inter-
estingly the reaction could be tuned to give 1,4-oxazines
11-13 by employing either a propargyl alcohol having
internal acetylenic linker (entries 9 and 10), or by increas-
ing the steric crowding around the aziridine framework
(entry 11).
In conclusion, we have presented a novel approach for the
preparation of 6-, 7-, and 8-member unsaturated hetero-
cycles having two heteroatoms through a Ag(I)-catalyzed
cascade reaction of aziridines/azetidines with propargyl
alcohols. Further work is underway in our laboratory to
broaden the scope of the reaction, and to explore the
mechanism.
Experimental Section
All reactions were carried out under an argon atmosphere in
flame-dried glassware with Schlenk techniques. Chromato-
graphic purifications were done with either 60-120 or 100-200
mesh silica gel. For reaction monitoring, precoated silica gel 60
F254 TLC sheets were used. Petroleum ether refers to the fraction
boiling in the range 60-80 °C. Dichloroethane was dried and
distilled prior to use.
Preparation of [Ag(COD)2]PF6. To a water solution of AgPF6
(0.5 mmol in 3 mL of water) was added a methanolic solution of
SCHEME 4
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Bera and Roy
JOCNote
1,5-cyclooctadiene (2 mmol in 0.5 mL of methanol) at room
temperature in the absence of light. Reaction was completed
just after 5 min and the residue was filtered and washed with
water and hexane. The white solid was then dried under
vacuum. It was then crystallized from benzene/ dichloro-
methane solvent system. Anal. Calcd for C16H26OAgPF6: C,
39.44; H, 5.38. Found: C, 39.46; H, 5.04. MS (m/z)
[Ag(C8H12)2]þ at 323 at cone voltage 15 V, [Ag(C8H12)]þ at
215 at cone voltage 35 V.
General Procedure. A mixture of N-tosylaziridine (0.5 mmol),
propargyl alcohol (0.5 mmol), and [Ag(COD)2]PF6 (2 mol %) in
2 mL of dry dichloroethane was stirred at room temperature.
After 1-3 h (vide TLC), when aziridine was nearly diminished
then Cs2CO3 (1 equiv) was added and the reaction mixture was
heated at 80 °C for 3-5 h. After completion of the reaction (vide
TLC) the mixture was diluted with water (5 mL) and extracted
with dichloromethane. The combined organic layers were dried
over anhydrous sodium sulfate and concentrated in vacuum,
then the resulting product was purified by column chromato-
graphy on silica gel (100-200 mesh, ethyl acetate-petroleum
ether, 1:5 v/v) to afford the corresponding heterocycles in good
yields.
Preparation of 5-Tosyl-2,5,5a,6,7,8,9,9a-octahydrobenzo[b]-
[1,4]oxazepine [3]. A mixture of N-tosylcyclohexyl aziridine
(0.5 mmol, 125 mg), propargyl alcohol (0.5 mmol, 30 μL), and
[Ag(COD)2]PF6 (0.01 mmol, 4.6 mg) in 2 mL of dichloroethane
was stirred at room temperature. After 1 h when aziridine was
totally diminished Cs2CO3 (0.5 mmol, 163 mg) was added and
the reaction mixture was heated at 80 °C for 3 h. After comple-
tion of the reaction (vide TLC), the reaction mixture was diluted
with water (5 mL) and extracted with dichloromethane. The
combined organic layers were dried over anhydrous sodium
sulfate and concentrated in vacuum, then the resulting product
was purified by column chromatography on silica gel (100-200
mesh, ethyl acetate-petroleum ether, 1:5). The yield was ob-
tained in 72% (110.5 mg). 1H NMR (400 MHz, CDCl3) δ
1.31-1.46 (m, 4H), 1.68-1.75 (m, 2H), 1.92 (t, J = 5.2 Hz,
1H), 2.28-2.32 (m, 1H), 2.39 (s, 3H), 3.20-3.26 (m, 1H),
3.60-3.66 (m, 1H), 3.89-4.02 (m, 2H), 4.98-5.01 (m, 1H),
6.28 (d, J = 9.2 Hz, 1H), 7.25 (d, J = 8 Hz, 2H), 7.71 (d, J =
8.4 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 21.6, 24.8, 29.7,
33.3, 34.6, 67.9, 69.2, 78.4, 120.5, 124.9, 127.2, 129.3, 136.3, 143.2;
DEPT-135 NMR 21.6 (CH3), 24.8 (CH2), 29.7 (CH2), 33.2 (CH2),
34.6 (CH2), 67.9 (CH), 69.2 (CH2), 78.3 (CH), 120.6 (CH), 124.8
(CH), 127.2 (CH), 129.4 (CH). Anal. Calcd for C16H21NO3S: C,
62.51; H, 6.89; N, 4.56. Found: C, 62.49; H, 6.92; N, 4.54.
(15) See the Supporting Information for details.
(16) (a) Wang, L.; Liu, Q. B.; Wang, D. S.; Li, X.; Han, X. W.; Xiao, W. J.;
Zhou, Y. G. Org. Lett. 2009, 11, 1119. (b) Wang, S.; Zhu, Y.; Wang, Y.; Lu,
P. Org. Lett. 2009, 11, 2615.
Acknowledgment. We thank DST (financial support to
S.R.) and CSIR (fellowship to M.B.).
(17) ESI-MS spectrum of [Ag(COD)2]PF6 in ES(þ) mode showed peaks
corresponding to both [Ag(COD)2]þ and [Ag(COD)]þ at low conþe voltage
(15 V). On the other hand at high cone voltage (35 V), [Ag(COD)] was the
only species present. This suggests the lability of [Ag(COD)2]þ in solution.
Supporting Information Available: Experimental proce-
dures, characterization data, and 1H and 13C NMR spectra
for all new compounds and crystallographic data for 4, 9, and
12. This material is available free of charge via the Internet at
http://pubs.acs.org.
˚
Note that the metal-olefin bond distance in [Ag(COD)2]PF6 (2.50 A) is
longer compared to other d10 analogues such as Cu, Ni, and Pt; see:
(a) Vander, J.; Hende, H.; Baird, W. C. J. Am. Chem. Soc. 1963, 85, 1003.
(b) Schunn, R. A.; Ittel, S. D.; Cushing, M. A. Inorg. Synth. 1990, 28, 94.
(c) Howard, J. A. K. Acta Crystallogr. 1982, B38, 2896.
J. Org. Chem. Vol. 74, No. 22, 2009 8817