Pd-NHC catalyzed conjugate addition versus the mizoroki-heck reaction

Article abstract of DOI:10.1002/chem.201003643

Ace of base: A catalytic system is presented that, solely by choice of the base, selectively switches between conjugate addition and the Mizoroki-Heck reaction of aryl halides with Michael acceptors (see scheme; R, R′=alkyl, aryl). For conjugate addition reactions, this avoids the preparation and use of organometallics.

Full text of DOI:10.1002/chem.201003643

COMMUNICATION
DOI: 10.1002/chem.201003643
Pd–NHC Catalyzed Conjugate Addition versus the Mizoroki–Heck Reaction
Aditya L. Gottumukkala,[a] Johannes G. de Vries,*[a, b] and Adriaan J. Minnaard*[a]
The transition-metal-catalyzed conjugate addition of aryl
organometallic reagents constitutes a cornerstone in organic
chemistry.[1] The use of copper has been very successful for
the conjugate addition of hard organometallics like
Grignard reagents.[2] However, rhodium-[3] and palladium-
catalyzed[4] conjugate additions of soft organometallics are
becoming increasingly popular due to their broad functional
group tolerance, mild reaction conditions, and wide scope.
Irrespective of the catalysis, the required organometallic re-
agents, like Grignards,[5] organozincs,[6] and boronic acids[7]
or their derivatives, are nearly invariably synthesized from
the corresponding aryl halides. It is therefore remarkable
that little attention has been given to the direct use of aryl
halides in metal-catalyzed conjugate addition reactions; all
the more so because the closely related Mizoroki–Heck[8] re-
action has been studied and applied extensively. Thus, it
would be a significant advance if, as in the latter reaction,
the umpolung of the aryl halide would take place by the
transition-metal catalyst. For the result to be a conjugate ad-
dition, a reductive cleavage would be necessary, as opposed
to the b-hydride elimination that takes place during the Miz-
oroki–Heck reaction (Scheme 1).
The conjugate addition product in palladium-catalyzed
Mizoroki–Heck reactions is in fact regularly observed as a
side product,[9,10] and this derailing, sometimes referred to as
the “reductive Heck reaction”, has been partially appreciat-
ed in the literature in inter-[11] and intramolecular[12] cases.
However, it remains unclear whether this involves a bona
fide conjugate addition, or a Mizoroki–Heck reaction fol-
lowed by reduction, the latter also being commonly ob-
served.[13] Surprisingly, only the group of Cacchi[11b,d,14] has
studied the conjugate addition of aryl halides in some detail
for the addition of 4-iodoanisole to benzalacetone (1).
Herein, we report an efficient catalyst system that, under
mild conditions, allows the reaction to be steered completely
either to conjugate addition or to Mizoroki–Heck reaction
solely by the base used. Our results indicate that in the con-
jugate addition, the Pd–alkyl complex is reduced by the
Bu3N via a b-hydride elimination reductive–elimination se-
quence.
Building upon the reaction conditions described by
Cacchi et al. (Table 1, entry 1), we scrutinized both the prod-
uct composition and the reaction parameters. In addition to
the expected conjugate addition product 3a (62% yield),
the Mizoroki–Heck product 3b, and 4,4’-dimethoxybiphenyl
(3c) were also obtained (Scheme 2). Careful analysis re-
vealed that varying amounts of 4-methoxybutyrophenone
Table 1. Pd-catalyzed conjugate addition to benzalacetone.[a]
Entry
Pd source
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
[Pd2A(dba)3]·CHCl3
[Pd2A(dba)3]·CHCl3
[Pd2A(dba)3]·CHCl3
[Pd2A(dba)3]·CHCl3
mol%
Ligand
mol%
3a[b]
1[c]
2
G
10
5
5
2.5
2.5
2.5
2.5
5
PPh3
PPh3
PPh3
PPh3
24
11
11
11
11
10
10
–
–
–
–
–
62
60
54
62
nd[f]
58
64
nd
74
82
58
54
R
3[d]
4
E
Scheme 1. Reductive cleavage affords the conjugate addition product,
whereas b-hydride elimination leads to the Mizoroki–Heck product.
G
N
5[e]
6[e]
7[e]
8[e]
9[e,i]
10[e]
11[e]
12[e]
E
PPh3
N
Tol-BINAP[g]
G
rac-BINAP
PEPPSI-IPr[h]
PdII–NHC[j]
Pd0–NHC
–
–
–
–
–
3
1.5
0.2
0.02
Pd0–NHC[k]
Pd0–NHC[l]
[a] A. L. Gottumukkala, Prof. Dr. J. G. de Vries, Prof. Dr. A. J. Minnaard
Stratingh Institute for Chemistry, University of Groningen
Nijenborgh 4, 9747 AG, Groningen (The Netherlands)
Fax : (+31)50-363-429
[a] Reaction conditions: 1 (1.14 mmol), 2 (2.7 mmol), Bu3N (5.1 mmol.),
CF3COOH (3 mmol), Bu4NI (0.11 mmol), 808C, DMF, N2, 18 h. [b] Yield
of isolated product. [c] Reaction completed in 12 h. [d] 1.4 mmol of 2
used. [e] CF3COOH and Bu4NI omitted. [f] Incomplete conversion after
18 h; significant amounts of Mizoroki–Heck product observed; nd=not
E-mail: A.J.Minnaard@rug.nl
[b] Prof. Dr. J. G. de Vries
DSM Innovative Synthesis BV, P.O. Box 18, 6160 MD
Geleen (The Netherlands)
E-mail: Hans-JG.Vries-de@dsm.com
determined.
[g] BINAP=2,2’-bis(diphenylphosphino)-1,1’-binaphthyl.
[h] PEPPSI-Ipr, see reference [21]. [i] KOtBu (10 mol%) added, with 2-
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201003643.
propanol as a
solvent.[15] [j] NHC=N-heterocyclic carbene. [k] 1008C.
[l] 1208C.
Chem. Eur. J. 2011, 17, 3091 – 3095
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3091

isolated product is probably
caused by decomposition of the
substrate at a higher tempera-
ture.
Although these findings indi-
cate that protonolysis of the in-
termediate alkyl–Pd does not
take place (as the reaction also
occurs in the absence of an
acid), mechanistic studies by
Friestad and Branchaud[22] on
the Cacchi system suggested
Scheme 2. Distribution of products, using the conditions in reference [14c].
that the absence of acid would
result in the initial formation of
the Mizoroki–Heck product 3b,
(3d)[16] and 1-butenyl-4-methoxybenzene (3e)[17] were also
formed, resulting from the oxidation of tributylamine. Low-
ering the catalyst loading led to only a slightly increased re-
action time (Table 1, entry 2), whereas using either a Pd0
precursor or bisphosphines instead of PPh3 did not improve
the outcome (Table 1, entries 3–7). Experiments performed
in the absence of Pd or Bu3N led to full recovery of the
starting material. Taken together, this strongly suggests that
the colloidal Pd particles[18] are the catalytically active spe-
cies. To find a well-defined catalyst that would also be di-
rectly relevant for enantioselective conjugate addition, we
next turned our attention to carbene ligands.
followed by its reduction to 3a by an accumulation of the
Pd–H species formed from NBu3. With our system however,
no formation of 3b was observed during the entire course of
the reaction.[23] In addition, when 0.5 mmol of 4b was added
to the reaction mixture, it could be recovered completely
without the formation of 4a, thus indicating that there is no
accumulation of the Pd–H species. These observations con-
vincingly suggest that 3a is formed by arylation, followed by
reduction of the palladium. The role of Bu3N in this reac-
tion, in addition to being the reductant, could be to keep
the alkyl palladium species coordinatively saturated thereby
avoiding b-hydride elimination from the substrate, yet facili-
tating b-hydride elimination from the NBu3. Varying the
electron density on the aryl halide (Table 2) showed that
The use of PdII–NHC[19] resulted in an increase in yield
compared to the other palladium catalysts (Table 1, entry 9
Table 2. Substituted aryl iodides RC6H4I in the conjugate addition reac-
tion. See Supporting Information for details.
Entry
R
Product
Yield[a] [%]
1
2
3
4
5
6
4-MeO
H
3-Cl
3-Br
4-Cl
4-Br
3a
3 f
3g
3h
3i
82
83
52
56
58
63
3j
[a] Yield of the isolated product.
vs. entries 1–7). However, the use of Pd0–NHC, as reported
by Beller et al.,[20] enabled 3a to be isolated in a higher
yield (82%, Table 1, entry 10), with no formation of 3b ob-
served. The comparatively lower activity of PdII–NHC could
result from the fact that it needs to be reduced to Pd0 prior
to catalysis. Using PEPPSI–Ipr,[21] also a PdII–N-heterocyclic
carbene catalyst, resulted in a similar outcome (Table 1,
entry 8).
Surprisingly, it was found that this reaction gives the same
outcome without the addition of trifluoroacetic acid and tet-
rabutylammonium iodide; this result greatly simplifies the
catalytic system (Table 1, entries 5–10). Lowering the cata-
lyst loading 10-fold (0.2 mol%, Table 1, entry 11) or 100-
fold (0.02 mol%, entry 12) still resulted in significant yields,
albeit at higher temperatures. The decrease in the yield of
electron-poor aryl iodides also perform reasonably in the re-
action. Replacement of iodides with aryl bromides or chlor-
ides under the reaction conditions, only led to recovery of
the starting materials.
After having achieved selective conjugate addition, we
aimed for selective formation of the Mizoroki–Heck product
additionally, by choosing bases that are incapable of reduc-
ing Pd through hydride donation. Among the bases studied,
cesium pivalate proved to be very efficient, perhaps due to
its solubility in organic solvents. In short, complete reversal
of selectivity to the Mizoroki–Heck product was achieved,
proving that the base is key in tuning the selectivity.
As is invariably found with Heck reactions to b-substitut-
ed enones, a mixture of double-bond isomers was ob-
tained,[24] which is a strong indication for a fast palladium C-
3092
www.chemeurj.org
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2011, 17, 3091 – 3095

Conjugate Addition versus the Mizoroki–Heck Reaction
COMMUNICATION
bound-to-O-bound equilibrium. At present, it is unclear
whether in the conjugate addition the reduction takes place
from the C- or O-bound palladium species. To complete our
studies on benzalacetone, the reaction was performed under
microwave irradiation, which enabled complete conversion
and selectivity in the conjugate addition and the Mizoroki–
Heck product in 30 min, with yields identical to those ob-
tained with conventional heating.
Subsequently, the scope of this switchable catalyst system
was explored (Table 3). Both linear and cyclic enones could
be converted selectively into either the conjugate addition
or the Mizoroki–Heck product depending on the base. The
selective conjugate addition to cyclohexenone and cyclohep-
tenone is noteworthy, especially since the Mizoroki–Heck
reaction on cycloheptenone with aryl halides has not been
reported to date (and did not take place in our hands, de-
spite several attempts). In addition, the trans,trans-dibenzyli-
deneacetone smoothly undergoes bis-conjugate addition to
9a in 74% yield and Mizoroki–Heck reaction to 9b in an
excellent 92% yield. When d-mannitol-derived 10[25] was
employed,
a diastereoselective conjugate addition took
place affording a 5:1 mixture in favor of the anti product
(Scheme 3). In contrast, a,b-unsaturated esters, amides, and
nitriles yielded only their corresponding Mizoroki–Heck
products, regardless of the base used.
To stretch the utility of the approach, we studied the b-ni-
trostyrenes (Table 4); a substrate class that until now has
failed to undergo the Mizoroki–Heck reaction.[26] Intriguing-
ly, although the attempted Miz-
oroki–Heck reaction led to re-
covered starting materials, the
Table 3. Selectivity governed by base.
conjugate addition reaction
readily took place when Bu3N
was used as the base (Table 4).
Conjugate addition
product[a]
Yield Substrate
[%]
Mizoroki–Heck
product[a,b]
Yield
[%]
This questions the current opin-
ion[26] that lack of substrate co-
ordination or sequestration of
Pd by the nitro group are the
reasons for the failure of these
substrates in the Mizoroki–
Heck reaction. The yield is
strongly dependent on the elec-
tronic properties of the sub-
strate; for example, 2,3-dime-
thoxy-b-nitrostyrene provided
13a in 64% yield, whereas 1-
nitro-1-cyclohexene did not
react and was recovered
(Table 4, entry3 vs. entry6).
3a 82
3b 83
4a 73
4b 80
In summary,
a
catalytic
5a 63
5b 84
6b 64
system has been developed,
which, by choice of the base, se-
lectively switches between con-
jugate addition and Mizoroki–
Heck reaction of aryl halides
and Michael acceptors. For con-
jugate addition reactions, this
avoids the preparation and use
of organometallics, rendering
the reaction easier to operate.
Reductive cleavage of Pd, in-
stead of protonolysis, is pro-
posed to release the product.
For the first time, the reaction
is extended to b-nitrostyrenes;
a class of substrates unamena-
ble to the corresponding Mizor-
oki–Heck reaction. The reac-
tion is completed in 30 min
under microwave irradiation,
and can be performed with
6a 56
7a 69
–
–
–
8a 92
8b 71
9a 74
9b 92
[a] Yield of isolated product. [b] Obtained as a mixture of E/Z isomers. nd=not determined.
Chem. Eur. J. 2011, 17, 3091 – 3095
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
3093

A. J. Minnaard, J. G. de Vries et al.
bined, dried over anhydrous MgSO4,
and concentrated in vacuo. The con-
centrate was loaded directly or ad-
sorbed onto silica prior to loading
onto a silica gel column and eluted.
General procedure for the Mizoroki–
Heck reaction: A flame-dried Schlenk
tube, equipped with screwcap and stir-
rer bar, was placed under nitrogen,
Scheme 3. Diastereoselective conjugate addition.
and charged with aryl iodide
(1 mmol), enone (1.5 mmol), cesium
pivalate (2 mmol) followed by Pd0–
NHC catalyst (1.5 mol%) as a stock
Table 4. Conjugate addition to b-nitrostyrenes.
solution (0.017 mmol in 1 mL DMF). The Schlenk tube was then alternat-
ed through three cycles of vacuum and nitrogen, and placed into a pre-
heated oil bath at 808C. Upon completion (as judged by GC/MS and/or
TLC) the reaction mixture was cooled to room temperature and poured
into HCl (v/v) solution (10%, 10 mL) and extracted with diethyl ether
(3ꢁ25 mL). The organic extracts were combined, dried over anhydrous
MgSO4, and concentrated in vacuo. The concentrate was loaded directly,
or adsorbed onto silica, before loading onto a silica gel column.
Entry
1
Substrate
Product
Yield [%][b]
28
11a
Acknowledgements
2
3
12a
13a
54
64
Prof. B. L. Feringa is thanked for helpful discussions. This research has
been performed within the framework of the CatchBio Program. The au-
thors gratefully acknowledge the support of the Smart Mix Program of
the Netherlands Ministry of Economic Affairs and the Netherlands Min-
istry of Education, Culture and Science, DSM and Organon.
Keywords: base
elimination · palladium
·
conjugate addition
·
carbenes.
·
4
5
14a
15a
21
38
[1] J. F. Hartwig, Organotransition Metal Chemistry: From Bonding to
Catalysis, University Science Book, Sausalito, 2009.
[2] a) T. Jerphagnon, M. G. Pizzuti, A. J. Minnaard, B. L. Feringa,
Chem. Soc. Rev. 2009, 38, 1039–1075; b) S. R. Harutyunyan, T. den
Hartog, K. Geurts, A. J. Minnaard, B. L. Feringa, Chem. Rev. 2008,
108, 2824–2852.
6
–
–
[a] Yield of isolated product.
[3] a) T. Hayashi, K. Yamasaki, Chem. Rev. 2003, 103, 2829–2844; b) K.
Yoshida, T. Hayashi in Modern Rhodium-Catalyzed Organic Reac-
tions (Ed.: P. A. Evans), Wiley-VCH, Weinheim, 2005, pp. 55–71.
[4] a) A. Gutnov, Eur. J. Org. Chem. 2008, 4547–4554; b) N. Miyaura,
Synlett 2009, 2039–2050.
[5] G. S. Silverman in Handbook of Grignard Reagents (Eds.: G. S. Sil-
verman, P. E. Rakita), Marcel-Dekker, New York, 1996, pp. 9–21.
[6] P. Knochel, R. D. Singer, Chem. Rev. 1993, 93, 2117–2188.
[7] D. G. Hall in Boronic Acids (Ed.: D. G. Hall), Wiley-VCH, Wein-
heim, 2006, pp. 1–99.
good diastereoselectivity. This conjugate addition reaction
has considerable scope, including cases where the Mizoroki–
Heck reaction fails. This reaction awaits its enantioselective
version, which is a challenge we are currently working on.
The results presented here are an excellent prelude to such
a development.
[8] a) M. Oestreich, The Mizoroki–Heck Reaction, Wiley, New York,
2009; b) I. P. Beletskaya, A. V. Cheprakov, Chem. Rev. 2000, 100,
3009–3066.
[9] a) Y. Fall, H. Doucet, M. Santelli, Tetrahedron 2009, 65, 489–495;
b) H. Hagiwara, Y. Eda, K. Morohashi, T. Suzuki, M. Ando, N. Ito,
Tetrahedron Lett. 1998, 39, 4055–4058; c) J. P. Genet, E. Blart, M.
Savignac, Synlett 1992, 715–717.
[10] For a discussion of the formation of Mizoroki–Heck product as a
side product in the rhodium-catalyzed conjugate addition of boronic
acids, see: a) G. Zou, Z. Wang, J. Zhu, J. Tang, Chem. Commun.
2003, 2438–2439; b) G. Zou, J. Guo, Z. Wang, W. Huang, J. Tang,
Dalton Trans. 2007, 3055–3064.
[11] a) G. E. Stokker, Tetrahedron Lett. 1987, 28, 3179–3182; b) S.
Cacchi, A. Arcadi, J. Org. Chem. 1983, 48, 4236–4240; c) S. C. Clay-
ton, A. C. Regan, Tetrahedron Lett. 1993, 34, 7493–7496; d) S.
Experimental Section
General procedure for conjugate addition: A flame-dried Schlenk tube,
equipped with screw cap and stirrer bar, was placed under nitrogen, and
charged with aryl iodide (2.72 mmol), enone (1.14 mmol), followed by
Pd0–NHC catalyst (1.5 mol%) as a stock solution (0.017 mmol in 1 mL
DMF), and n-tributylamine (5.1 mmol) by using a syringe. The Schlenk
tube was then alternated through three cycles of vacuum and nitrogen,
and placed into a preheated oil bath at 808C. Upon completion (as
judged by GC/MS and/or TLC) the reaction mixture was cooled to room
temperature and poured into HCl (v/v) solution (10%, 10 mL) and ex-
tracted with diethyl ether (3ꢁ25 mL). The organic extracts were com-
3094
www.chemeurj.org
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2011, 17, 3091 – 3095

Conjugate Addition versus the Mizoroki–Heck Reaction
COMMUNICATION
Cacchi, F. Gasparrini, P. Pace, C. Villani, Synlett 2000, 650–652;
e) H. Naito, S. Ohsuki, M. Sugimori, R. Atsumi, M. Minami, Y. Na-
kamura, M. Ishii, K. Hirotani, E. Kumazawa, A. Ejima, Chem.
Pharm. Bull. 2002, 50, 453–462; f) U. S. Sørensen, T. J. Bleisch,
A. E. Kingston, R. A. Wright, B. G. Johnson, D. D. Schoepp, P. L.
Ornstein, Bioorg. Med. Chem. 2003, 11, 197–205.
[17] Product 3e probably formed by a b-NBu2 elimination in the course
of the Mizoroki–Heck reaction of iodoanisole with the enamine,
which resulted from the oxidation of NBu3; see: J. Muzart, J. Mol.
Catal. A 2009, 308, 15–24.
[18] J. G. de Vries, Dalton Trans. 2006, 421–429.
[19] a) E. A. B. Kantchev, G. R. Peh, C. Zhang, J. Y. Ying, Org. Lett.
2008, 10, 3949–3952; b) E. A. B. Kantchev, J. Y. Ying, Organometal-
lics 2009, 28, 289–299.
[12] A. Minatti, X. Zheng, S. L. Buchwald, J. Org. Chem. 2007, 72, 9253–
9258.
[13] a) P. Mangeney, C. Pays, Tetrahedron Lett. 2003, 44, 5719–5722;
b) M. Ichikawa, M. Takahashi, S. Aoyagi, C. Kibayashi, J. Am.
Chem. Soc. 2004, 126, 16553–16558.
[14] a) S. Cacchi, G. Palmieri, Tetrahedron 1983, 39, 3373–3383; b) S.
Cacchi, F. Latorre, G. Palmieri, J. Organomet. Chem. 1984, 268,
c48–c51; c) A. Amorese, A. Arcadi, E. Bernocchi, S. Cacchi, S. Cer-
rini, W. Fedeli, G. Ortar, Tetrahedron 1989, 45, 813–828.
[15] M. S. Viciu, R. A. Kelly, E. D. Stevens, F. Naud, M. Studer, S. P.
Nolan, Org. Lett. 2003, 5, 1479–1482.
[16] Compound 3d is formed by the Heck reaction of iodoanisole with
the enamine resulting from the oxidation of tributylamine, followed
by hydrolysis upon workup. For similar examples, see: a) J. Ruan, X.
Li, O. Saidi, J. Xiao, J. Am. Chem. Soc. 2008, 130, 2424–2425;
b) F. R. S. Clark, R. O. C. Norman, C. B. Thomas, J. Chem. Soc.
Perkin Trans. 1 1975, 121–125.
[20] K. Selvakumar, A. Zapf, A. Spannenberg, M. Beller, Chem. Eur. J.
2002, 8, 3901–3906.
[21] M. G. Organ, G. A. Chass, D.-C. Fang, A. C. Hopkinson, C. Valente,
Synthesis 2008, 2776–2797.
[22] G. K. Friestad, B. B. Branchaud, Tetrahedron Lett. 1995, 36, 7047–
7050.
[23] Determined by taking GC samples at regular intervals.
[24] V. Calꢂ, A. Nacci, A. Monopoli, P. Cotugno, Angew. Chem. 2009,
121, 6217–6219; Angew. Chem. Int. Ed. 2009, 48, 6101–6103.
[25] S. Ohira, T. Ida, M. Moritani, T. Hasegawa, J. Chem. Soc. Perkin
Trans. 1 1998, 293–297.
[26] S. E. Denmark, M. E. Schnute, J. Org. Chem. 1995, 60, 1013–1019.
Received: December 17, 2010
Published online: February 8, 2011
Chem. Eur. J. 2011, 17, 3091 – 3095
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
3095