An efficient [2 + 2 + 1] synthesis of 2,5-disubstituted oxazoles via gold-catalyzed intermolecular alkyne oxidation

Article abstract of DOI:10.1021/ja2029188

The first efficient intermolecular reaction of gold carbene intermediates generated via gold-catalyzed alkyne oxidation has been realized using nitriles as both the reacting partner and the reaction solvent, offering a generally efficient synthesis of 2,5-disubstituted oxazoles with broad substrate scope. The overall reaction is a [2 + 2 + 1] annulation of a terminal alkyne, a nitrile, and an oxygen atom from an oxidant. The reaction conditions are exceptionally mild, and a range of functional groups are easily tolerated. With complex and/or expensive nitriles, only 3 equiv could be sufficient to achieve serviceable yields in the absence of any solvent and using only 1 mol % BrettPhosAuNTf₂ as the catalyst.

Full text of DOI:10.1021/ja2029188

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An Efficient [2 þ 2 þ 1] Synthesis of 2,5-Disubstituted Oxazoles via
Gold-Catalyzed Intermolecular Alkyne Oxidation
Weimin He, Chaoqun Li, and Liming Zhang*
Department of Chemistry and Biochemistry, University of California, Santa Barbara, California 93106, United States
S Supporting Information
b
Scheme 1. Gold-Catalyzed Alkyne Oxidation: Application to
Intermolecular Oxazole Synthesis
ABSTRACT: The first efficient intermolecular reaction of
gold carbene intermediates generated via gold-catalyzed
alkyne oxidation has been realized using nitriles as both
the reacting partner and the reaction solvent, offering a
generally efficient synthesis of 2,5-disubstituted oxazoles
with broad substrate scope. The overall reaction is a [2 þ 2þ 1]
annulation of a terminal alkyne, a nitrile, and an oxygen
atom from an oxidant. The reaction conditions are excep-
tionally mild, and a range of functional groups are easily
tolerated. With complex and/or expensive nitriles, only 3
equiv could be sufficient to achieve serviceable yields in the
absence of any solvent and using only 1 mol % BrettPhos-
AuNTf2 as the catalyst.
would react with the carbene intermediates, leading to unwanted
side reactions.12 We surmised that nitriles,13 especially when
used as the solvent, could react with the gold carbene inter-
mediate rapidly enough that these side reactions would be largely
suppressed, therefore allowing the replacement of hazardous
R-diazoketones with alkynes in oxazole synthesis;14 moreover, the
overall reaction would be a desirable [2 þ 2 þ 1] annulation15 of
the alkyne, the nitrile, and an oxygen atom from an oxidant
(Scheme 1).
he oxazole ring with its 2- and 5-positions substituted with
T
aryl or alkyl groups is an important structure found in
various natural products1 and compounds with biological activ-
ities. These oxazoles can also serve as versatile substrates for
various synthetic transformations, including the formation of
fully substituted oxazoles.2 Among many strategies developed for
their synthesis,3,4 one-pot [3 þ 2] annulations involving nitriles
and R-functionalized ketones are arguably the simplest and most
desirable. The R-functionalized ketones can be R-diazoketones5
or those generated in situ via ketone R-oxidation. However, R-
diazoketones are hazardous, potentially explosive, and seldom
commercially available, and synthesing and handling them are
often challenging. For the in situ generation approach, strong
acids (e.g., TfOH)6 and/or stoichiometric amounts of some-
times toxic metal salts7 must be used; morever, the reaction
scopes are mostly limited to 5-aryloxazoles. Needless to say, there
is still much need for a convergent synthesis of 2,5-disubstituted
oxazoles from readily available and benign substrates with the
following features: exceptionally mild reaction conditions, ex-
cellent functional group tolerance, and broad reaction scope.
Herein we discolse a gold-catalyzed oxidative approach that
largely meets the need via a [2 þ 2 þ 1] annulation.
We began the study using acetonitrile as the solvent.16 To
develop conditions that would be highly compatible with various
functional groups, acidic additives were avoided in the screening.
With Ph3PAuNTf217 as the catalyst, different N-oxides were tested
at 60 °C (Table 1, entries 1ꢀ6). While we were surprised that even
commercially available pyridine N-oxide worked to some extent
(entry 1), 8-methylquinoline N-oxide (2e) was the best among the
oxidants examined (entry 5). Other gold catalysts, though more
expensive, worked equally well (entries 7ꢀ9). The reaction
proceeded very slowly when run at ambient temperature (entry
10); however, it could be accelerated by using MsOH (entry 11),
suggesting that 8-methylquinoline may coordinate with the gold
catalyst, albeit reversibly. The special catalytic role of gold in this
reaction was substantiated by the inability of AgNTf2 and HNTf2 to
catalyze this reaction (entries 12 and 13).
The scope of this reaction was then examined (Table 2). First,
acetonitrile was used as the nitrile source. As shown in entries
1ꢀ10 and 14ꢀ18, a range of terminal alkynes were allowed, and
the reaction yields were mostly g80%. Various functional groups
were readily tolerated, including an unprotected HO (entry 2); a
free carboxylic acid moiety (entry 5); acid-labile groups such as
TBSO (entry 3), THP (entry 4), and Boc (entry 7); an oxidizable
PhS group (entry 6); an alkyl chloride (entry 8); and aryl groups
having different electronic and steric natures (entries 1 and 15ꢀ18).
In the case of arylacetylenes, ortho subsitution did decrease the
reaction yield substantially, likely due to steric hindrance, although
We recently showed that stable, benign, and often commer-
cially available alkynes can replace hazardous R-diazoketones for
the generation of gold carbene intermediates.8 These intermedi-
ates, generated via gold-catalyzed oxidation9ꢀ11 of alkynes by
pyridine/quinoline N-oxides, can undergo intramolecular OꢀH8a,b
or NꢀH insertions8c and 1,2-CꢀH insertions8d that lead to
synthetically useful products (Scheme 1). However, no inter-
molecular reaction of these gold carbene intermediates has been
reported, let alone one that is synthetically efficient. A major
concern is that the presence of oxidants and its reduced form
Received: March 31, 2011
Published: May 12, 2011
r
2011 American Chemical Society
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Table 1. Screening of Gold Catalysts and Reaction Conditionsa
entry
catalyst
oxidant
conditions
conv. (%)
yield (%)b
1
2
Ph3PAuNTf2
Ph3PAuNTf2
Ph3PAuNTf2
Ph3PAuNTf2
Ph3PAuNTf2
Ph3PAuNTf2
BrettPhosAuNTf2
IPrAuNTf2
2a
2b
2c
2d
2e
2f
60 °C, 3 h
60 °C, 3 h
60 °C, 3 h
60 °C, 3 h
60 °C, 3 h
60 °C, 3 h
60 °C, 3 h
60 °C, 3 h
60 °C, 3 h
rt, 6 days
69
54
51
50
13
59
98c
85
90
93
98
87
98
0
3
24
4
64
5
100
100
100
100
100
92
6
7
2e
2e
2e
2e
2e
2e
2e
8
d
9
(RO)3PAuNTf2
10
11
12
13
Ph3PAuNTf2
Ph3PAuNTf2
AgNTf2
rt, overnight, MsOH (1.1 equiv)
60 °C, 3 h
60 °C, 3 h
100
0
HNTf2
0
0
a In vial; [1] = 0.1 M. b Estimated by 1H NMR spectroscopy using diethyl phthalate as an internal reference. c Isolated yield of 94%. d R = 2,4-(t-Bu)2Ph.
the reaction was still serviceable (entry 18). With propargyl
alcohols, their derivatives, and propargyl amides as the alkyne
substrates, our previously reported intramolecular trapping of the
R-oxo gold carbene intermediates8a,c became a major side reaction,
resulting in low yields of the desired oxazoles. Similarly, homo-
propargyl alcohols8b were not good alkyne substrates; however,
protected ones worked just fine (entry 4). In addition, propargyl
bromide and homopropargyl bromide were not good substrates.
Interestingly, double annulation occurred smoothly with hepta-
1,6-diyne, affording bisoxazole 1o in 81% yield (entry 14).
This reaction also permitted the use of acetylenes substituted
with a bulky tert-butyl group (entry 11), an alkenyl group (entry
12) and a cyclopropyl group (entry 13), and serviceable to good
yields were obtained. For these entries, propionitrile or isobutyr-
onitrile was used in order to make the oxazole products less volatile.
These cases established that acetonitrile could be readily replaced
with another nitrile as the reaction solvent. Indeed, besides these two
aliphatic nitriles (entries 11ꢀ13, 19, and 20), benzonitrile (entries
21 and 22) and phenylacetonitrile (entry 23) reacted smoothly,
affording functionalized oxazoles in good yields. With 1,6-hexane-
dinitrile as the solvent, a selective monoannulation gave oxazole
nitrile 1y in an acceptable yield (entry 24).
These results encouraged us to decrease the loading of the gold
catalyst, as its concentration was high with 5% loading in the
absence of any solvent. To our delight, a nearly identical yield
was realized using only 1 mol % BrettPhosAuNTf2. To test
whether this observation could be extended to sophisticated
and hence expensive nitriles, we synthesized nitriles 3 and 4,
and they participated in the reaction equally well when only 3
equiv was used in the absence of any solvent (eqs 2 and 3).
Moreover, most of the excess nitrile could be recovered, and
the reaction yields based on the recovered nitrile were fairly
good (68%) to very good (81%). Again, both TBSO and CꢀC
double bonds were readily tolerated under the mild reaction
conditions.
Having demonstrated the broad reaction scope obtained using
nitriles as the solvent, our attention turned to situations where
the nitrile is expensive and/or not commercially available. We
initially used nevertheless cheap propionitrile to probe whether
other solvents could be used. With 3 equiv of the nitrile, solvents
such as toluene and chlorobenzene at 0.1 M concentration led to
poor yields (<20%), but a serviceable yield (50%) was realized with
8c,18
6 equiv of chlorobenzene as the solvent and BrettPhosAuNTf2
as the catalyst (eq 1). Moreover, the reaction yield was improved
to a respectable 60% when no solvent was used, which is remarkable
considering the high concentrations of 2e and its reduced form (i.e., 8-
methylquinoline). In comparison, the reaction yield was 85% when
propionitrile was used as the solvent (alkyne concentration 0.1 M).
This method provides a facile synthesis19 of pimprinaphine1c from
protected 3-ethynylindole 520 and phenylacetonitrile in two steps
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Table 2. Reaction Scopea,b
various nitriles, which affords 2,5-disubstituted oxazoles in
mostly good to excellent yields. The reaction scope is broad,
and a range of terminal alkynes and nitriles are allowed. For
expensive and/or commercially unavailable nitriles, the nitrile
does not have to be used as the solvent; use of only 3 equiv of the
nitrile is sufficient to obtain a serviceable yield in the absence of
any solvent and with only 1 mol % BrettPhosAuNTf2 as the
catalyst. The reaction conditions are exceptionally mild, and
even sensitive functional groups such as THP and Boc are easily
tolerated. The overall reaction is a convergent [2 þ 2 þ 1]
annulation.
’ ASSOCIATED CONTENT
S
Supporting Information.
Experimental procedures
b
and compound characterization data. This material is available
free of charge via the Internet at http://pubs.acs.org.
’ AUTHOR INFORMATION
Corresponding Author
zhang@chem.ucsb.edu
’ ACKNOWLEDGMENT
We thank the NSF (CAREER Award CHE-0969157), Amgen,
and UCSB for generous financial support and Sigma-Aldrich for
the kind gift of BrettPhos.
’ REFERENCES
(1) For selected examples, see: (a) Debono, M.; Molloy, R. M.;
Occolowitz, J. L.; Paschal, J. W.; Hunt, A. H.; Michel, K. H.; Martin, J. W.
J. Org. Chem. 1992, 57, 5200–5208. (b) Crow, W.; Hodgkin, J. Aust. J.
Chem. 1968, 21, 3075–3077. (c) Koyama, Y.; Yokose, K.; Dolby, L. J.
Agric. Biol. Chem. 1981, 45, 1285–1287. (d) Rudi, A.; Stein, Z.; Green, S.;
Goldberg, I.; Kashman, Y.; Benayahu, Y.; Schleyer, M. Tetrahedron 1994,
35, 2589–2592. (e) Fontana, G. Curr. Bioact. Compd. 2010, 6, 284–308.
(f) Davyt, D.; Serra, G. Mar. Drugs 2010, 8, 2755–2780.
(2) For selected cases, see: (a) Clapham, B.; Sutherland, A. J. J. Org.
Chem. 2001, 66, 9033–9037. (b) Chatani, N.; Fukuyama, T.; Tatamidani, H.;
Kakiuchi, F.; Murai, S. J. Org. Chem. 2000, 65, 4039–4047.
(3) For a review, see: Boyd, G. V. Sci. Synth. 2001, 11, 383–480.
(4) For recent reports of oxazole synthesis, see: (a) Zhang, J.;
Coqueron, P.-Y.; Ciufolini, M. A. Heterocycles 2011, 82, 949–980.
(b) Counceller, C. M.; Eichman, C. C.; Proust, N.; Stambuli, J. P. Adv.
Synth. Catal. 2011, 353, 79–83. (c) Cano, I.; Alvarez, E.; Nicasio, M. C.;
Perez, P. J. J. Am. Chem. Soc. 2011, 133, 191–193. (d) Austeri, M.; Rix,
D.; Zeghida, W.; Lacour, J. Org. Lett. 2011, 13, 1394–1397. (e) Wan, C.;
Zhang, J.; Wang, S.; Fan, J.; Wang, Z. Org. Lett. 2010, 12, 2338–2341. (f)
Wan, C.; Gao, L.; Wang, Q.; Zhang, J.; Wang, Z. Org. Lett. 2010,
12, 3902–3905. (g) Saito, A.; Matsumoto, A.; Hanzawa, Y. Tetrahedron
Lett. 2010, 51, 2247–2250. (h) Lai, P.-S.; Taylor, M. S. Synthesis
2010, 1449–1452. (i) Jiang, H.-F.; Huang, H.-W.; Cao, H.; Qi, C.-R.
Org. Lett. 2010, 12, 5561–5563.
a [1] = 0.1 M. b Isolated yields are given. c Overnight. d 2.6 equiv of 2e.
e 10 mol % Au.
(eq 4), highlighting the synthetic utility of this gold catalysis.
Apparently, the TMS group in 5 was removed during the reaction,
presumably before the oxidation. Notably, without the Boc protec-
tion in 5, the reaction was low yielding and not clean.
(5) For reviews/books on the reactions of R-diazoketones, see: (a)
Doyle, M. P.; McKervey, M. A.; Ye, T. Modern Catalytic Methods for
Organic Synthesis with Diazo Compounds: From Cyclopropanes to Ylides;
Wiley: New York, 1998. (b) Doyle, K. J.; Moody, C. J. Tetrahedron 1994,
50, 3761–3772. (c) Davies, H. M. L.; Beckwith, R. E. J. Chem. Rev. 2003,
103, 2861–2903. (d) Ye, T.; McKervey, M. A. Chem. Rev. 1994,
94, 1091–1160.
(6) For examples, see: (a) Ishiwata, Y.; Togo, H. Tetrahedron 2009,
65, 10720–10724. (b) Varma, R. S.; Kumar, D. J. Heterocycl. Chem. 1998,
35, 1533–1534.
In summary, we have developed the first intermolecular reaction
of R-oxo gold carbenes generated via alkyne oxidation with
8484
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(7) For examples, see: (a) Lee, J. C.; Hong, T. Tetrahedron Lett.
1997, 38, 8959–8960. (b) Lee, J. C.; Song, I.-G. Tetrahedron Lett. 2000,
41, 5891–5894. (c) Nagayoshi, K.; Sato, T. Chem. Lett. 1983, 12, 1355–
1356.
(8) (a) Ye, L.; He, W.; Zhang, L. J. Am. Chem. Soc. 2010,
132, 8550–8551. (b) Ye, L.; Cui, L.; Zhang, G.; Zhang, L. J. Am. Chem.
Soc. 2010, 132, 3258–3259. (c) Ye, L.; He, W.; Zhang, L. Angew. Chem.,
Int. Ed. 2011, 50, 3236–3239. (d) Lu, B.; Li, C.; Zhang, L. J. Am. Chem.
Soc. 2010, 132, 14070–14072.
(9) With various tethered oxidants, gold complexes can catalyze
intramolecular oxidations of alkynes, and gold carbene intermediates are
typically invoked. For references, see: (a) Li, G.; Zhang, L. Angew. Chem.,
Int. Ed. 2007, 46, 5156–5159. (b) Shapiro, N. D.; Toste, F. D. J. Am.
Chem. Soc. 2007, 129, 4160–4161. (c) Yeom, H. S.; Lee, J. E.; Shin, S.
Angew. Chem., Int. Ed. 2008, 47, 7040–7043. (d) Cui, L.; Peng, Y.; Zhang,
L. J. Am. Chem. Soc. 2009, 131, 8394–8395. (e) Cui, L.; Zhang, G.; Peng,
Y.; Zhang, L. Org. Lett. 2009, 11, 1225–1228. (f) Yeom, H. S.; Lee, Y.;
Lee, J. E.; Shin, S. Org. Biomol. Chem. 2009, 7, 4744–4752. (g) Davies,
P. W.; Albrecht, S. J. C. Angew. Chem., Int. Ed. 2009, 48, 8372–8375.
(h) Cui, L.; Zhang, L. Chem. Commun. 2010in press. (i) Yeom, H. S.;
Lee, Y.; Jeong, J.; So, E.; Hwang, S.; Lee, J. E.; Lee, S. S.; Shin, S. Angew.
Chem., Int. Ed. 2010, 49, 1611–1614. (j) Jadhav, A. M.; Bhunia, S.; Liao,
H.-Y.; Liu, R.-S. J. Am. Chem. Soc. 2011, 133, 1769–1771. (k) Yeom, H.-
S.; So, E.; Shin, S. Chem.—Eur. J. 2011, 17, 1764–1767.
(10) For a recent intermolecular case using pyridine N-oxide, see:
(a) Davies, P. W.; Cremonesi, A.; Martin, N. Chem. Commun. 2011,
47, 379–381. For an intermolecular gold-catalyzed nitrene transfer, see:
(b) Li, C.; Zhang, L. Org. Lett. 2011, 1738–1741.
(11) When sulfoxides are used as external oxidants, the gold carbene
intermediates may not be formed. For references, see: (a) Cuenca, A. B.;
Montserrai, S.; Hossain, K. M.; Mancha, G.; Lledos, A.; Medio-Simon,
M.; Ujaque, G.; Asensio, G. Org. Lett. 2009, 11, 4906–4909. (b) Li,
C.-W.; Pati, K.; Lin, G.-Y.; Sohel, S. M. A.; Hung, H.-H.; Liu, R.-S. Angew.
Chem., Int. Ed. 2010, 49, 9891–9894.
(12) For intermolecular oxidation of gold carbene intermediates, see:
(a) Witham, C. A.; Mauleon, P.; Shapiro, N. D.; Sherry, B. D.; Toste,
F. D. J. Am. Chem. Soc. 2007, 129, 5838–5839. (b) Taduri, B. P.; Sohel,
S. M. A.; Cheng, H.-M.; Lin, G.-Y.; Liu, R.-S. Chem. Commun. 2007,
2530–2532.
(13) For examples of gold catalysis using nitriles as substrates, see:
(a) Ramꢀon, R. S.; Marion, N.; Nolan, S. P. Chem.—Eur. J. 2009,
15, 8695–8697. (b) Ibrahim, N.; Hashmi, A. S. K.; Rominger, F. Adv.
Synth. Catal. 2011, 353, 461–468.
(14) For oxazole synthesis via gold-catalyzed cyclization of propargyl
amides, see: (a) Weyrauch, J. P.; Hashmi, A. S. K.; Schuster, A.; Hengst,
T.; Schetter, S.; Littmann, A.; Rudolph, M.; Hamzic, M.; Visus, J.;
Rominger, F.; Frey, W.; Bats, J. W. Chem.—Eur. J. 2010, 16, 956–963
and accompanying Supporting Information. (b) Hashmi, A. S. K.;
Weyrauch, J. P.; Frey, W.; Bats, J. W. Org. Lett. 2004, 6, 4391–4394.
(c) Hashmi, A. S. K.; Rudolph, M.; Schymura, S.; Visus, J.; Frey, W. Eur.
J. Org. Chem. 2006, 4905–4909.
(15) Trisubstituted oxazoles can be formed via annulation of internal
alkynes and acetonitrile in the presence of PhTeO(OTf), albeit with a
limited scope and moderate efficiencies. See: Fukumoto, T.; Aso, Y.;
Otsubo, T.; Ogura, F. J. Chem. Soc., Chem. Commun. 1992, 1070–1072.
(16) For early studies using acetonitrile as the solvent, see:
(a) Hashmi, A. S. K.; Schwarz, L.; Choi, J.-H.; Frost, T. M. Angew.
Chem., Int. Ed. 2000, 39, 2285–2288. (b) Hashmi, A. S. K.; Frost, T. M.;
Bats, J. W. J. Am. Chem. Soc. 2000, 122, 11553–11554.
(17) Mꢀezailles, N.; Ricard, L.; Gagosz, F. Org. Lett. 2005, 7, 4133–
4136.
(18) Fors, B. P.; Watson, D. A.; Biscoe, M. R.; Buchwald, S. L. J. Am.
Chem. Soc. 2008, 130, 13552–13554.
(19) Roy, S.; Haque, S.; Gribble, G. W. Synthesis 2006, 3948–3954.
(20) Oakdale, J. S.; Boger, D. L. Org. Lett. 2010, 12, 1132–1134.
8485
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