Practical synthesis of linear α-iodo/bromo-α,β-unsaturated aldehydes/ketones from propargylic alcohols via Au/Mo bimetallic catalysis

Article abstract of DOI:10.1021/ol901346k

Image Presented An efficient synthesis of α-iodo/bromo-α, β-unsaturated aldehydes/ketones directly from propargylic alcohols is described. This reaction is catalyzed collaboratively by two metal complexes, Ph₃PAuNTf₂ and MoO₂

Full text of DOI:10.1021/ol901346k

ORGANIC
LETTERS
2009
Vol. 11, No. 16
3646-3649
Practical Synthesis of Linear r-Iodo/
Bromo-r,ꢀ-unsaturated Aldehydes/
Ketones from Propargylic Alcohols via
Au/Mo Bimetallic Catalysis
Longwu Ye and Liming Zhang*,†
Department of Chemistry, UniVersity of NeVada, Reno, NeVada 89557
lzhang@chem.unr.edu
Received June 23, 2009
ABSTRACT
An efficient synthesis of r-iodo/bromo-r,ꢀ-unsaturated aldehydes/ketones directly from propargylic alcohols is described. This reaction is
catalyzed collaboratively by two metal complexes, Ph3PAuNTf2 and MoO2(acac)2, and Ph3PO as an additive helps suppress undesired enone/
enal formation. Notable features of this method include low catalyst loadings, mild reaction conditions, and mostly good to excellent
diastereoselectivity. In comparison with our previously developed method based on propargylic acetate substrates, this chemistry omits the
need to prepare acetate derivatives and, moreover, has a much broader substrate scope.
Propargylic carboxylates, prepared from propargylic alcohols
and activated carboxylic acids, are arguably the most versatile
substrates1 for gold and platinum catalysis,2 and some of
their gold-catalyzed reactions resulted in the formation of
products without retaining the acyl group.1c,d,g,3 For those
reactions, it is in theory possible to replace the acyl group
with an in situ installed and subsequently cleavable surrogate
or equivalent in a catalytic fashion. In this manner, significant
economic and environmental benefits can be garnered with
shortened synthetic routes and less chemical waste generated
(Scheme 1).
Scheme 1. Carboxyl Group Surrogate for Gold-Catalyzed
Reactions of Propargylic Carboxylates
† Current address: Department of Chemistry & Biochemistry, University
of California, Santa Barbara, CA 93106-9510. E-mail: zhang@
chem.ucsb.edu.
(1) For selected examples, see: (a) Miki, K.; Ohe, K.; Uemura, S. J.
Org. Chem. 2003, 68, 8505–8513. (b) Zhang, L. J. Am. Chem. Soc. 2005,
127, 16804–16805. (c) Zhang, L.; Wang, S. J. Am. Chem. Soc. 2006, 128,
1442–1443. (d) Johansson, M. J.; Gorin, D. J.; Staben, S. T.; Toste, F. D.
J. Am. Chem. Soc. 2005, 127, 18002–18003. (e) Marion, N.; Diez-Gonzalez,
S.; de Fremont, P.; Noble, A. R.; Nolan, S. P. Angew. Chem., Int. Ed. 2006,
45, 3647–3650. (f) Buzas, A.; Gagosz, F. J. Am. Chem. Soc. 2006, 128,
12614–12615. (g) Dudnik, A. S.; Schwier, T.; Gevorgyan, V. Org. Lett.
2008, 10, 1465–1468. (h) Luo, T.; Schreiber, S. L. Angew. Chem., Int. Ed.
2007, 46, 8250–8253. (i) Zou, Y.; Garayalde, D.; Wang, Q. R.; Nevado,
C.; Goeke, A. Angew. Chem., Int. Ed. 2008, 47, 10110–10113. (j) Cho,
E. J.; Lee, D. S. AdV. Synth. Catal. 2008, 350, 2719–2723. (k) Lu, L.; Liu,
X. Y.; Shu, X. Z.; Yang, K.; Ji, K. G.; Liang, Y. M. J. Org. Chem. 2009,
74, 474–477.
Last year, Akai and co-workers reported a bimetallic
catalysis4 using a combination of Ph3PAuCl/AgOTf5 and
MoO2(acac)2 (Scheme 2). In this efficient Meyer-Schuster
10.1021/ol901346k CCC: $40.75
Published on Web 07/28/2009
 2009 American Chemical Society

Though efficient, the reaction required propargylic acetates
as substrates and, moreover, did not work well with substrates
without substitution at either end of the propargyl moiety.
We reasoned that a Mo complex such as MoO2(acac)2 could
replace the acetyl moiety in this chemistry, similar to Akai’s
case, allowing the formation of R-halo-R,ꢀ-unsaturated
carbonyl products directly from propargylic alcohols and
likely with an improved scope (Scheme 3).
Scheme 2. Akai’s Chemistry and Our Conceived Mechanism
Scheme 3. Preparation of R-Halo-R,ꢀ-unsaturated Carbonyl
Compounds from Propargylic Alcohol: Design
reaction, several features are noteworthy: mild reaction
conditions (mostly at room temperature), low catalyst load-
ings (1 mol % for both Au and Mo complexes), and a broad
substrate scope.
Although Meyer-Schuster reactions catalyzed only by
gold complexes6 have been reported, the propargylic alcohol
substrates invariably contained features capable of substan-
tially stabilizing carbon cations. The broad scope and the
ease of Akai’s chemistry calls for, in our opinion, a
mechanism similar to that of propargylic carboxylates, where
a gold-catalyzed 3,3-rearrangement1b,c occurs en route to
enone formation.3a The difference is, as in our conceived
mechanism (Scheme 2), that the oxomolybdenum moiety acts
as an equivalent of the carbonyl group. Due to the labile
nature of the RO-Mo bond, intermediate 1 was generated
in situ and the Mo complex was rendered catalytic.
We first studied the formation of R-iodo enones/enals using
MoO2(acac)2 and Ph3AuNTf2 as the catalyst combination
and anhydrous CH2Cl2 as solvent. To our delight, R-iodo
enone 3 was indeed formed from propargylic alcohol 2 at
room temperature in 3 h (Table 1, entry 1). The drawback
8
Table 1. Bimetallic Au/Mo Catalysis: Conditions Optimization
We were attracted to the synthetic advantage of this
revelation as propargylic carboxylates in a range of gold
catalysis could be replaced with their precursors (i.e.,
propargylic alcohols) and thus decided to look into applying
this approach to some of the chemistry previously developed
in our laboratory.
3
entrya
additive
yield (%)b Z/Ec 4 (%)
1
2
3
4
5
6
7
8
9
10
54
72
69
6/1
36
12
28
<2
<2
9
We recently reported a preparative method of linear
R-iodo/bromo-R,ꢀ-unsaturated ketones based on gold ca-
talysis using propargylic acetate substrates.3b,d These func-
tionalized enones are versatile synthetic intermediates and
can be readily converted to a range of R-substituted enones
via transition metal-catalyzed cross-coupling reactions.7
DMSO (5 mol %)
DMF (5 mol %)
HMPA (5 mol %)
Ph3PO (5 mol %)
Ph3PO (1 mol %)
Ph3PO (5 mol %), no gold
no gold
24/1
11/1
26/1
16/1
12:1
18/1
80
>98d
71
13e
3e
<1
Ph3PO (5 mol %), no Mo
no Mo
7e
<1
<1
(2) For selected reviews on gold catalysis, see: (a) Hashmi, A. S. K.;
Rudolph, M. Chem. Soc. ReV. 2008, 37, 1766–1775. (b) Arcadi, A. Chem.
ReV. 2008, 108, 3266–3325. (c) Li, Z.; Brouwer, C.; He, C. Chem. ReV.
2008, 108, 3239–3265. (d) Gorin, D. J.; Sherry, B. D.; Toste, F. D. Chem.
ReV. 2008, 108, 3351–3378. (e) Skouta, R.; Li, C.-J. Tetrahedron 2008,
64, 4917–4938. (f) Jimenez-Nunez, E.; Echavarren, A. M. Chem. ReV. 2008,
108, 3326–3350. (g) Patil, N. T.; Yamamoto, Y. Chem. ReV. 2008, 108,
3395–3442. (h) Fu¨rstner, A.; Davis, P. W. Angew. Chem., Int. Ed. 2007,
46, 3410–3449. (i) Zhang, L.; Sun, J.; Kozmin, S. A. AdV. Synth. Catal.
2006, 348, 2271–2296. (j) Ma, S.; Yu, S.; Gu, Z. Angew. Chem., Int. Ed.
2006, 45, 200–203.
7e
a Reaction concentration was 0.05 M. Estimated by H NMR using
diethyl phthalate as internal reference. c The geometries of 3 were determined
by NOESY1D experiments. d 98% isolated yield. e The rest of the starting
material remained unreacted.
b
1
was the competitive formation of enone 4. While other metal
complexes such as VO(acac)2 and MeReO3 failed to improve
this reaction, we turned to modify MoO2(acac)2. It was
recently reported that dinuclear molybdenum complexes
Mo2O5(acac)2L2 (L ) DMF, Ph3PO, DMSO, H2O, HMPA,
etc.) could be readily prepared from MoO2(acac)2 and polar
compounds (i.e., L) in 96% ethanol.9 While our attempts to
(3) (a) Yu, M.; Li, G.; Wang, S.; Zhang, L. AdV. Synth. Catal. 2007,
349, 871–875. (b) Yu, M.; Zhang, G.; Zhang, L. Org. Lett. 2007, 9, 2147–
2150. (c) Zhao, J.; Hughes, C. O.; Toste, F. D. J. Am. Chem. Soc. 2006,
128, 7436–7437. (d) Yu, M.; Zhang, G.; Zhang, L. Tetrahedron 2009, 65,
1846–1855.
(4) Egi, M.; Yamaguchi, Y.; Fujiwara, N.; Akai, S. Org. Lett. 2008, 10,
1867–1870.
(5) AgOTf was used to generate Ph3PAu+ OTf- and presumably does
not participate in the catalysis.
(6) (a) Engel, D. A.; Dudley, G. B. Org. Lett. 2006, 8, 4027–4029. (b)
Ramo´n, R. S.; Marion, N.; Nolan, S. P. Tetrahedron 2009, 65, 1767–1773.
(7) For a review, see: Negishi, E. J. Organomet. Chem. 1999, 576, 179–
194.
(8) Mezailles, N.; Ricard, L.; Gagosz, F. Org. Lett. 2005, 7, 4133–4136.
(9) Pedrosa, M. R.; Escribano, J.; Aguado, R.; D´ıez, V.; Sanz, R.; Arna´iz,
F. J. Polyhedron 2007, 26, 3695–3702.
Org. Lett., Vol. 11, No. 16, 2009
3647

Table 2. Reaction Scope for the Formation of R-Iodo Enones/
Enals
Table 3. Reaction Scope for the Formation of R-Bromo Enones/
Enals
a The substrate concentration was 0.05 M. b Isolated yield. c The yield
of the corresponding enone is shown in parentheses. d Reaction time: 11 h.
e 5 mol % of Au(PPh3)NTf2, 5 mol % of MoO2(acac)2, and 15 mol % of
Ph3PO were used.
excellent yield with 5 mol % of the additive, while significant
enone formation was observed with 1 mol % (entry 6). The
role of Ph3PO in the reaction, though not clear at this point,
is likely to modify MoO2(acac)2 instead of Ph3PAuNTf2
(comparing entries 7, 8 and 9, 10). Notably, the reaction did
not proceed well using only one of the catalysts (entries
7-10).
With the optimized mild reaction conditions in hand, the
scope of this reaction was promptly studied. As shown in
Table 2, the reaction scope was broad and substantially
improved over that of our previous method3b,d based on
propargylic acetates (vida supra). Besides propargylic alco-
hols with substititions at both ends of the propargyl moiety
(i.e., R1 or R2 * H and R3 * H, entries 1-8, 13, and 14),
substrates with R1 ) R2 ) H (entries 10-12) worked
smoothly, affording 1-iodovinyl ketones efficiently. More-
over, when R3 ) H, R-iodo enal 6i was isolated in 73% yield
(entry 9). Notable is that R-iodo enals are versatile synthetic
substrates and their syntheses frequently require multiple
steps10 or strong reaction conditions11 or were limited by
substrate scope.12 For functional group tolerance, aryl groups
(entries 4-7, 10, and 11), benzyl/methyl ethers (entries 7,
8, and 11), and ester (entry 10) were allowed although a
TBS ether appeared to be labile under the reaction conditions.
The reaction yields were generally good to excellent, and
enone formation was mostly minimal. In some cases, more
catalysts were required to drive the reactions to completion
in acceptable time periods (entries 7-11). For the double-
bond geometry, good to excellent Z-selectivities were
observed except for substrates with phenyl substitution (Z/E
) 6:1, entries 4 and 5). In comparison, R-iodo enone 6d
a The substrate concentration was 0.05 M. b Isolated yield. c The yield
of the corresponding enone was shown in parentheses. d Reaction time: 15 h.
e 2 mol % of Au(PPh3)NTf2, 2 mol % of MoO2(acac)2, and 10 mol % of
Ph3PO were used.
prepare these complexes in pure form always met with
difficulty, we screened these polar compounds as additives
to the reaction. To our delight, the formation of enone 4 was
significantly suppressed with DMSO (entry 2) and almost
completely prevented with HMPA (entry 4) or Ph3PO (entry
5). In the case of Ph3PO, the reaction proceeded with an
3648
Org. Lett., Vol. 11, No. 16, 2009

was formed without much stereoselectivity (Z/E ) 1.2/1)
using the acetate of 5d.3b,d
In comparison to our previously developed method based
on propargylic acetate substrates, this chemistry omits the
need to prepare acetate derivatives and, moreover, has a much
broader substrate scope.
This reaction protocol could be readily applied to the
synthesis of R-bromo enones/enals by replacing NIS with
NBS (Table 3).3d,13 However, the reactions proceeded slowly
with 1 mol % of catalysts (e.g., 38 h for 5a). By increasing
the catalyst/additive loadings, all of the reactions were
complete in less than 12 h and afforded products with good
yields. Moreover, excellent diastereoselectivities were ob-
served in the cases of 5a and 5i.
Acknowledgment. We thank the NSF (CAREER award
CHE-0748484 and UNR) for generous financial support and
Mr. Guozhu Zhang and Ms. Soma Maitra from UNR and
Ms. Katie Miller (REU student) from Seattle Pacific Uni-
versity for some preliminary studies.
Supporting Information Available: Experimental pro-
cedures and full spectroscopic data for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
Attempts to extend this chemistry to the synthesis of
R-chloro/fluoro analogues were not successful, and further
studies in this direction are currently ongoing.
In summary, we have developed a highly efficient syn-
thesis of linear R-iodo/bromo-R,ꢀ-unsaturated ketones/alde-
hydes from propargylic alcohols. In this chemistry, two metal
complexes, Ph3PAuNTf2 and MoO2(acac)2, catalyze this
reaction collaboratively, and Ph3PO is used as an additive
to suppress undesired enone/enal formation. Notable features
of this method include low catalyst loadings, mild reaction
conditions, and mostly good to excellent diastereoselectivity.
OL901346K
(10) Shibahara, S.; Fujino, M.; Tashiro, Y.; Takahashi, K.; Ishihara, J.;
Hatakeyama, S. Org. Lett. 2008, 10, 2139–2142.
(11) Chen, S.; Wang, J. J. Org. Chem. 2007, 72, 4993–4996.
(12) Antonioletti, R.; D’Auria, M.; Piancatelli, G.; Scettri, A. Tetrahe-
dron Lett. 1981, 22, 1041–1042.
(13) Hashmi, A. S. K.; Ramamurthi, T. D.; Rominger, F. J. Organomet.
Chem. 2009, 694, 592–597.
Org. Lett., Vol. 11, No. 16, 2009
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