Mild and ligand-free Pd(II)-catalyzed conjugate additions to hindered γ-substituted cyclohexenones

Article abstract of DOI:10.1021/ol300794a

Ligand-free cationic Pd(II) catalyst with NaNO₃ as an additive is a highly active catalytic system for conjugate additions to sterically hindered γ-substituted cyclohexenones. More challenging γγ- and βγ-substrates also react well to produce products with quaternary centers in good dr. The conjugate additions occur in a diastereoselective fashion under mild, practical and air-stable conditions, using readily available commercial reagents.

Full text of DOI:10.1021/ol300794a

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Mild and Ligand-Free Pd(II)-Catalyzed
Conjugate Additions to Hindered
γ-Substituted Cyclohexenones
James A. Jordan-Hore, James N. Sanderson, and Ai-Lan Lee*
School of Engineering and Physical Sciences, Heriot-Watt University,
Edinburgh EH14 4AS, Scotland, United Kingdom
a.lee@hw.ac.uk
Received March 28, 2012
ABSTRACT
Ligand-free cationic Pd(II) catalyst with NaNO3 as an additive is a highly active catalytic system for conjugate additions to sterically hindered
γ-substituted cyclohexenones. More challenging γγ- and βγ-substrates also react well to produce products with quaternary centers in good dr. The
conjugateadditionsoccur ina diastereoselectivefashionunder mild, practical and air-stable conditions, using readily available commercialreagents.
Metal-catalyzed conjugate addition to R,β-unsaturated
carbonyl acceptors is a powerful tool for the construc-
tion of CꢀC bonds.1 For example, copper-catalyzed1c,d
and rhodium-catalyzed1aꢀc conjugate additions are well-
known and widely used methods of constructing CꢀC
bonds. Despite their indisputable utility in the synthetic
chemists’ toolkit, there are still some drawbacks to the
currently available methods. For example, the Cu-cata-
lyzed conjugate additions often involve subzero tempera-
tures as well as air- and moisture-sensitive organometallic
reagents that require rigorously anhydrous reaction condi-
tions. Due to the use of such organometallic reagents, some
functional groups cannot be tolerated. The alternative Rh-
catalyzed additions overcame this issue by utilizing air- and
water-stable organoboron reagents. However, this advance
comes with other drawbacks, including the high cost of Rh
catalysts, as well as the lower tolerance of steric hindrance:
because effective coordination of the acceptor to rhodium is
crucial for the reaction, acceptors that bear steric bulk in
proximity to the unsaturation will be less reactive.1a Thus,
γ-substituted cyclohexenones such as 1 (R1/R2 = alkyl or
aryl) are unsuitable substrates for thepopular Rh-catalyzed
reaction.4 Nevertheless, the products of conjugate addi-
tions to γ-substituted cyclohexenones 2 are useful building
blocks in organic synthesis;4bꢀd thus a mild, air-stable,
diastereoselective and practical procedure for the transfor-
mation of 1 to 2 would be an invaluable advancement.
Palladium(II)-catalyzed conjugate additions have re-
cently emerged asa cheaper alternative totheRh-catalyzed
reactions and can be tolerant of air and moisture, unlike
the more established Cu-catalyzed versions.2,3 Herein, we
disclose results to demonstrate that in addition to the
advantages mentioned above, a new ligandless cationic
Pd(II) system now allows for Pd(II)-catalyzed conjugate
additions which are also highly tolerant of steric hindrance.
The conditions are mild, efficient, and practical for
the diastereoselective conjugate additions to sterically
(2) For reviews, see ref 1a and: (a) Gutnov, A. Eur. J. Org. Chem.
2008, 4547. (b) Yamamoto, Y.; Nishikata, T.; Miyaura, N. Pure Appl.
Chem. 2008, 80, 807.
(3) For selected Pd-catalyzed conjugate additions, see: (a) Kikushima,
K.; Holder, J. C.; Gatti, M.; Stolz, B. M. J. Am. Chem. Soc. 2011, 133,
6902. (b) Brozek, L. A.; Sieber, J. D.; Morken, J. P. Org. Lett. 2011, 13,
995. (c) Lin, S.; Lu, X. Org. Lett. 2010, 12, 2536. (d) Xu, Q.; Zhang, R.;
Zhang, T.; Shi, M. J. Org. Chem. 2010, 75, 3935. (e) Lin, S.; Lu, X.
Tetrahedron Lett. 2006, 47, 7167. (f) Nishikata, T.; Yamamoto, Y.;
Miyaura, N. Chem. Lett. 2007, 36, 1442. (g) Nishikata, T.; Yamamoto,
Y.; Miyaura, N. Adv. Synth. Catal. 2007, 349, 1759. (h) Lu, X.; Lin., S.
J. Org. Chem. 2005, 70, 9651. (i) Gini, F; Hessen, B.; Minaard, A. J. Org.
Lett. 2005, 7, 5309. (j) Nishikata, T.; Yamamoto, Y.; Miyaura, N.
Organometallics 2004, 23, 4317. (k) Nishikata, T.; Yamamoto, Y.;
Miyaura, N. Angew. Chem., Int. Ed. 2003, 42, 2768.
(1) For selected recent reviews, see:(a) Berthon, G.; Hayashi, T.
Rhodium- and Palladium-Catalyzed Asymmetric Conjugate Additions.
ꢀ
In Catalytic Asymmetric Conjugate Reactions; Cordova, A., Ed.; Wiley-
VCH: Weinheim, 2010; pp 1ꢀ70. (b) Edwards, H. J.; Hargrave, J. D.;
Penrose, S. D.; Frost, C. G. Chem. Soc. Rev. 2010, 39, 2093. (c)
€
Christoffers, J.; Koripelly, G.; Rosiak, A.; Rossle, M. Synthesis 2007,
1279. (d) Alexakis, A.; Backvall, J. E.; Krause, N.; Pamies, O.; Dieguez,
M. Chem. Rev. 2008, 108, 2796.
r
10.1021/ol300794a
XXXX American Chemical Society

Table 1. Initial Studies: Conditions for Pd(II)-Catalyzed Con-
jugate Additions
Table 2. Screen of Additive Equivalents
entry boroxine NaNO3 (equiv) yield of 2c (%) yield 4b (%)
1
2
3a
3a
3a
3a
3a
3a
3b
3b
3b
3b
3b
3b
0
25
45
58
75
96
98
<5
<5
<5
83
86
95
20
20
15
11
6
0.05
0.1
0.2
0.5
1
3
temp
additive,
(1 equiv) yield of 2b (%)
4
entry conditions
X
(°C)
5
1
2
A
B
B
B
B
C
A
A
OMe
OMe
H
65
rt
rt
rt
rt
rt
rt
rt
rt
rt
83
6
3
25 conv
<5 conv
7
0
31
29
21
18
10
7
3
8
0.05
0.1
0.2
0.5
1
4
OMe
H
NaNO3
NaNO3
NaNO3
98
9
5
95
10
11
12
6
OMe
OMe
OMe
quant
20 conv
51 conv
0
7c
8c
9
NaNO3
NaNO3
NaNO3
a Commercial boronic acid was heated under vacuum to generate
boroxine, 0.67 equiv used. b Entries 1ꢀ6: determined by 1H NMR analysis
of the crude mixture. Entries 7ꢀ12: isolated yields. c Isolated yield.
No Pd cat. OMe
TfOH OMe
10
0
a Commercial aryl boronic acid was heated under vacuum to gen-
erate boroxine, 0.67 equiv used. b Isolated yields unless otherwise stated.
c ClCH2CH2Cl was used as solvent.
conversion, entry 2). Unfortunately, the same catalyst
provided no product 2b upon replacing boroxine 3a with
phenylboroxine 3b (entry 3). In order to improve the
conversion, a screen of different additives was carried out
(see the Supporting Information). To our surprise and
pleasure, addition of 1 equiv of inexpensive sodium nitrate
greatly enhanced the reaction to result in full conversion
and excellent yields of 2 (98% 2a, 95% 2b, entries 4 and 5).
To simplify the practical procedure even further, we in-
vestigatedthe reaction with in situ formation of the cationic
catalyst using only commercially available reagents, and to
our delight, the desired product 2a was formed in quanti-
tative yield (entry 6). Addition of NaNO3 also enhances the
neutral Pd(II) reaction (conditions A), but not as efficiently
(entries 7 and 8). A control with NaNO3 in the absence of
any Pd catalyst, or with only TfOH, provides no product 2
(entries 9 and 10), showing that the reaction is indeed
Pd-catalyzed. It should be noted that strictly anhydrous
or O2 free conditions are not necessary for conditions AꢀC;
the reactions were all carried out in air with commercial
solvents and are thus experimentally practical.
Next, we evaluated the effect of varying amounts of
NaNO3 additive in the reaction of 1a to 2a and 2b
(Table 2). Using the more reactive p-MeOC6H4-boroxine
3a, a clear increase in the yield of product 2a is observed as
the equiv of NaNO3 is gradually increased from 0 to 1
(entries 1ꢀ6). The slightly less reactive phenylboroxine 3b
produces no conjugate product 2b at all with 0, 0.05, and
0.1 equiv of NaNO3 (entries 7ꢀ9) but the yield improves
significantly with 0.2, 0.5, and 1 equiv of NaNO3 (entries
10ꢀ12).6
hindered γ-, γγ-, and βγ-substituted cyclic enones 14 by
utilizing a new ligandless Pd2þ/NaNO3 system.
Our investigations commenced with optimization of the
reaction conditions for the conjugate addition to γ-sub-
stituted cyclohexenone 1a (Table 1). Initially, neutral
Pd(II) catalysts were evaluated [Pd(OAc)2, 1,10-phenan-
throline, 65 °C, conditions A, entry 1] and were found to
provide the highest conversion and yield (83%).
Despite this initial result, we argued that it would be
preferable to develop a milder method without the need for
elevated temperatures. To this end, cationic Pd(II) com-
plexes were evaluated as possible catalysts, and we were
pleased to find Pd(MeCN)4(OTf)25 as a promising catalyst
for transforming 1a to 2a at room temperature (25%
(4) As far as we are aware, there are no examples of Rh-catalyzed 1,4-
additions to γ-alkyl/aryl-substituted cyclohexenones, and our attempts
to carry out Rh-catalyzed conjugate additions to 1a, 1g, and 1h led to no
reaction (see the Supporting Information). There is one isolated example
with Pd catalysis (1g, 60 °C, moderate 66% yield, ref 3e), but no
examples that would lead to diastereoselectivity were tested. As a
comparison, using these conditions (ref 3e) with more hindered 1h led
to no reaction (see the Supporting Information). All other methods for
these 1,4-additions to γ-substituted cyclohexenones involve air- and
moisture-sensitive cuprate addition conditions at subzero temperatures.
For example, see: (a) Nevill, C. R., Jr.; Fuchs, P. L. Synth. Commun.
1990, 20, 761. (b) William, A. D.; Kobayashi, Y. J. Org. Chem. 2002, 67,
8771. (c) Huffman, J. W.; Thompson, A. L. S.; Wiley, J. L.; Martin, B. R.
Bioorg. Med. Chem. 2008, 16, 322. (d) Piers, E.; Gavai, A. V. J. Org.
Chem. 1990, 55, 2380. (e) Lipshutz, B. H.; Wood, M. R. J. Am. Chem.
Soc. 1993, 115, 12625.
(5) Drent, E.; Van Broekhoven, J. A. M.; Doyle, M. J. J. Organomet.
Chem. 1991, 417, 235.
B
Org. Lett., Vol. XX, No. XX, XXXX

Table 3. Boroxine Scope
Table 4. γ,γγ,βγ-Substituted Cyclic Enone Scope
R (entries 1ꢀ11)
entry
reagent (entry 12)
time (h)
drc
yieldb (%)
1
2
Ph
18
5
15:1
12:1
95, 2b
98, 2a
83, 2c
88, 2d
91, 2e
85, 2f
98, 2g
89, 2h
89, 2i
84, 2j
73, 2k
0c
p-MeOC6H4
p-EtO2CC6H4
p-FC6H4
3
48
48
48
36
18
72
18
18
18
48
>20:1
12:1
4
5
p-BrC6H4
p-OHCC6H4
p-HOC6H4
m-O2NC6H4
m-MeC6H4
m-ClC6H4
o-MeOC6H4
PhB(OH)2
>20:1
>20:1
10:1
6
7
8
>20:1
>20:1
>20:1
>20:1
N/A
9
10
11
12
a Commercial boronic acids were either heated under vacuum or refluxed
under DeanꢀStark conditions to generate boroxine, 0.67 equiv used.
b Isolated yield. c Determined by 1H NMR analysis of the crude mixture.
As for the role of NaNO3, we observed that the gradual
increasein NaNO3 equivalents, and thus, the improvement
in the yield of 2 is also accompanied by a reduction in the
formation of biaryl side product 4, which is a common side
product in Pd(II)-catalyzed reactions with boronic acids/
boroxines.7 A control subjecting boroxine 3a to conditions
B in Table 1 without any substrate 1a provides (a) 100%
homocoupled 4a in the absence of NaNO3 and (b) only
30% conversion to 4a in the presence of NaNO3. There-
fore, we propose that one of the roles of NaNO3 as an
additive is the suppression of the homocoupling side
reaction,6 which is a significant side reaction especially
when hindered enones are employed as substrates.
With these optimized and mild conditions in hand,
we set out to investigate the scope of the aryl boroxine
substrates (Table 3). Pleasingly, a series of para-substituted
electron-donating and -withdrawing aryl boroxines react
smoothlytoprovide the products2aꢀgingood toexcellent
diastereoselectivitiesandyields(entries2ꢀ7). Evenbromo-
as well as unprotected formyl- and hydroxy-substituted
aryls add smoothly (entries 5ꢀ7); such functional groups
would be incompatible with the Cu-catalyzed conjugate
addition method (vide supra). Since the bromo function-
ality is tolerated under these Pd(II) conditions, these can be
a Determined by 1H NMR analysis of the crude mixture, anti/syn
ratio. b Isolated yields. c Reaction carried out at 0 °C for 48 h. d Reaction
warmed to 45 °C; no reaction at rt e 20 mol % cat.; with 10 mol %, the
yield is 64%. f 10 þ 5 mol % cat., g No NaNO3 was added.
(6) NaNO3 is only sparingly soluble in ClCH2CH2Cl. It should also
be noted that the use of Pd(MeCN)2(NO3)2 produces a poor yield (only
37% conv with 1a and 3a); thus, the NaNO3 additive in Table 2 is not
functioning by a simple anion exchange. See the SupportingInformation
for further studies regarding solubility and amount of NaNO3 required,
as well as further studies on the role of NaNO3.
introduced as a handle for further reaction through Pd(0)-
catalyzed cross-couplings. Ortho- and meta-substituted
(7) For example, see:Yoo, K. S.; Yoon, C. H.; Jung, K. W J. Am.
Chem. Soc. 2006, 128, 16384and references cited therein.
Org. Lett., Vol. XX, No. XX, XXXX
C

aryl boroxines also add in excellent dr and good yields (entries
8ꢀ11). During initial investigations, we observed a positive
correlation between the proportion of boroxine8 in the com-
mercial “boronic acid” reagents and the yield. A control
reaction using pure boronic acid PhB(OH)2 instead of the
boroxine produced no reaction (entry 12), indicating that the
active reagent in these reactions is indeed the boroxine.
Next, a series of γ-substituted cyclohexenones were
investigated (Table 4).9 An aromatic γ-substituent (1b)
compares favorably with 1a to produce 5 in excellent yield
and diastereoselectivity (91%, >20:1, entry 2). Reduction
of steric bulk of the γ substituent from i-Pr (1a) to benzyl
(1b) and n-octyl (1c) still produces an excellent yield of 6
and 7, respectively (92% and 94%), although the dr is
slightly lower (8:1, entries 3ꢀ4). Cooling the reaction to
0 °C improves the dr to 11:1 (entry 5). Pleasingly, even
bulky t-Bu is tolerated as a γ-substituent, producing
the anti diastereomer 8 exclusively in 75% yield (entry 6).
In order to demonstrate the practicality of the Pd(II)-
catalyzed method, a scaled up reaction (1 g of substrate
1e) was carried out with 5 mol % of the in situ formed
Pd(MeCN)4OTf2 catalyst to yield the desired product 8 in
a good 86% yield (Scheme 1).
catalyst (conditions D, no MeCN added). Gratifyingly,
these ligandless conditions proved excellent for the con-
jugate additions to bulky γγ-disubstituted cyclic enones
under mild conditions. Addition to 1g and 1h now occurs
smoothly under rt, and with a good 8:1 dr for 11 (entries 9
and 11). In comparison, the original neutral conditions A
(Table 1) require 60 °C for conversion with 1h and produce
11 with a poor 2.5:1 dr as a result (51% yield), showing the
importance of an active yet mild rt procedure. Pleasingly,
even the challenging β,γ-disubstituted cyclohexenone 1i
reacts under conditions D to form a β quaternary center in
12 with a good 8:1 dr and 76% yield (entry 12). At this point,
we decided to evaluate these new conditions D with our
original model substrate 1a and were delighted to find a
quantitative yield of 2b in less than 1 h (entry 13). Although
optimized for hindered γ-cycohexenones, conditions B/D are
also suitable for less hindered 1j2 (entry 14) and β-substituted
1k3a,c (entry 16), producing the desired products 13 and 14 in
good yields. Interestingly, the reaction works better without
NaNO3 for 1j (entry 15), suggesting that NaNO3 is only
necessary for challenging substrates where aryl homocou-
pling would otherwise be competitive, such as hindered
substrates 1aꢀi. Finally, if the use of chlorinated solvents is
a concern, preliminary studies show trifluorotoluene10 to be a
plausible alternative solvent with conditions D: reaction of 3a
with 1a produces 2a in 76% yield and 5.5:1 dr.
Scheme 1. Practical, Scaled Up In Situ Method
In conclusion, we have developed mild, high-yielding,
and diastereoselective (up to >20:1) Pd(II)-catalyzed con-
jugate additions to sterically hindered γ-,γγ- and βγ-sub-
stituted cyclohexenones, substrates which are too hindered
for Rh-catalyzed procedures. The Pd(II) procedure is not
only air-stable and practical but is also tolerant of func-
tional groups which are usually incompatible with the
more sensitive Cu-catalyzed procedures. Crucially, we have
developed a highly active, ligandless cationic Pd(II) system
and discovered that inclusion of sodium nitrate as an
additive greatly enhances the reactivity of the cationic Pd(II)
catalyst for conjugate additions. Future work will focus on
developing further uses for this catalyst system.
In order to push the reaction further, γγ-disubstituted
cyclic enones were evaluated as possible substrates (entries
7ꢀ11). While the reaction proceeded well with 1f (entry 7),
standard conditions B are no longer sufficient to promote
the reaction with 1g and 1h, reflecting the extra steric bulk
introduced by the γ quaternary center in these substrates.
However, the reaction proceeded smoothly with 1g upon
warmingto45°C (entry 8), but evenheatisnot sufficient to
promote the reaction of more hindered 1h (entry 10).
In an effort to develop an even more active catalyst
system for these difficult γγ-disubstituted cyclic enones, we
evaluated the in situ formation of ligandless cationic Pd(II)
Acknowledgment. We thank the Leverhulme Trust
(F/00 276/O) and Nuffield Undergraduate Bursary
(J.N.S.) for funding. EPSRC National Mass Spectrometry
Service Centre at Swansea is acknowledged for analytical
services. Johnson Matthey isgratefully acknowledged for a
generous loan of Pd(OAc)2.
Supporting Information Available.
Experimental
(8) Korich, A. L.; Iovine, P. M. Dalton Trans. 2010, 39, 1423.
(9) γ-Substituted cyclohexenone substrates can be synthesized in one
step from the corresponding cyclohexanone: (a) Diao, T.; Stahl, S. S.
J. Am. Chem. Soc. 2011, 133, 14566or via Robinson annulation. For
example, see: (b) Hagiwara, H.; Okobe, T. J. Chem. Soc., Perkin Trans.
1 2002, 895. See the Supporting Information for more details.
(10) Ogawa, A.; Curran, D. P J. Org. Chem. 1997, 62, 450.
procedures, spectroscopic data, and NMR spectra for
all new compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX