Palladium-catalyzed Minisci reaction with simple alcohols

Article abstract of DOI:10.1021/ol201774b

A palladium-catalyzed coupling of N-heterocycles with simple alcohols was achieved. The reaction is initiated by peroxide and does not require the use of stoichiometric acid for activation of the heterocycle.

Full text of DOI:10.1021/ol201774b

ORGANIC
LETTERS
2011
Vol. 13, No. 17
4581–4583
Palladium-Catalyzed Minisci Reaction
with Simple Alcohols
Camille A. Correia, Luo Yang, and Chao-Jun Li*
Department of Chemistry, McGill University, 801 Sherbrooke Street West, Montreal,
Quebec H3A 2K6, Canada
cj.li@mcgill.ca
Received July 2, 2011
ABSTRACT
A palladium-catalyzed coupling of N-heterocycles with simple alcohols was achieved. The reaction is initiated by peroxide and does not require
the use of stoichiometric acid for activation of the heterocycle.
CÀH activation of alcohols and ethers has garnered
much interest due to the ease of generating a new CÀC
bond and simple introduction of an oxygen-containing
functional group into the molecule at the same time.1
Although great progress has been made for the coupling
of alcohols to alkynes and alkenes, through a transfer
hydrogenative pathway,2 thedirectand selective activation
of the R sp3 CÀH of alcohols still remains particularly
challenging to chemists.
radical. In 2009, Liu5 and co-workers published a tert-
butyl hydroperoxide (TBHP) initiated addition of alcohols
to alkynes in the absence of metal catalysts.
Recently, Tu demonstrated the metal-catalyzed CÀC
coupling of alcohols and alkenes.6 The reaction could be
performed using Ru, Rh, or Pd catalysts, in the presence of
a strong Lewis acid (BF3 OEt2) for activation of the
alcohol. More recently, they were able to perform this
reaction with FeCl3.7
3
Early studies in this field by Minisci3 describe the
hydroxymethylation and hydroxyethylation of heterocyc-
lic bases, in the presence of peroxides and stoichiometric
amounts of acid, in moderate and low yields respectively.
In 2006, a Co(acac)2/N-hydroxyphthalimide (NHPI) cat-
alyzed addition of secondary alcohols to electron-deficient
alkynes was explored by Ishii.4 Similar to Minisci’s work,
this reaction was initiated by an R H-radical abstraction
from the alcohol by the phthalimide N-oxyl (PINO)
Figure 1. Palladium-catalyzed dehydrogenative coupling be-
tween ethanol and isoquinoline.
(1) Zhang, S.-Y.; Zhang, F.-M.; Tu, Y.-Q. Chem. Soc. Rev. 2011, 40,
1937.
We considered the possibility of a cross-coupling between
alcohols and N-heterocycles via metal catalysis, circumvent-
ing the need for stoichiomeric acid for protonation of
the heterocycle. Herein we describe a palladium-catalyzed
(2) For reviews, see: (a) Patman, R. L.; Bower, J. F.; Kim, I. S.;
Krische, M. J. Aldrichimica Acta 2008, 41, 95. (b) Bower, J. F.; Kim, I. S.;
Patman, R. L.; Krische, M. J. Angew. Chem., Int. Ed. 2009, 48, 34. (c)
Williams, V. M.; Leung, J. C.; Patman, R. L.; Krische, M. J. Tetrahedron
2009, 65, 5024.
(3) (a) Minisci, F. Synthesis 1973, 1. (b) Minisci, F; Vismara, A.;
Fontana, F.; Morini, G.; Serravalle, M. J. Org. Chem. 1986, 51, 476. (c)
Minisci, F; Cetterio, A.; Vismara, A.; Giordano, C. Tetrahedron Lett.
1985, 26, 617.
(4) Oka, R.; Nakayama, M.; Sakaguchi, S.; Ishii, Y. Chem. Lett.
2006, 35, 1104.
(6) (a) Shi, L.; Tu, Y.-Q.; Wang, M.; Zhang, F.-M.; Fan, C.-A.; Zhao,
Y.-M.; Xia, W.-J. J. Am. Chem. Soc. 2005, 127, 10836. (b) Jiang, Y.-J.;
Tu, Y.-Q.; Zhang, E.; Zhang, S.-Y.; Cao, K.; Shi, L. Adv. Synth. Catal.
2008, 350, 552. (c) Zhang, S.-Y.; Tu, Y.-Q.; Fan, C.-A.; Jiang, Y.-J.; Shi,
L.; Cao, K.; Zhang, E. Chem.;Eur. J. 2008, 14, 10201.
(5) Liu, Z.-Q.; Sun, L.; Wang, J.-G.; Han, J.; Zhao, Y.-K.; Zhou, B.
Org. Lett. 2009, 11, 1437.
(7) Zhang, S.-Y.; Tu, Y.-Q.; Fan, C.-A.; Zhang, F.-M.; Shi, L.
Angew. Chem., Int. Ed. 2009, 48, 8761.
r
10.1021/ol201774b
2011 American Chemical Society
Published on Web 08/09/2011

Minisci reaction of quinolines and isoquinolines with simple
alcohols (Figure 1).
A variety of nitrogen containing heterocycles were sub-
jected to these optimized conditions. Quinolines and iso-
quinolines were found to be acceptable substrates for this
reaction affording the product in moderate to good yields.
Owing to the lack of regioselectivity of quinoline and
6-methoxyquinoline, alkylation on the 2- and 4-positions
as well as bis-addition products were obtained (Table 2,
entries 4 and 5). As expected, the electron-rich substrate,
6-methoxyquinoline, provided the product in low yields.
On the other hand, the electron-poor substrate, methyl
3-isoquinolinecarboxylate, reacted smoothly and with
Table 1. Optimization of Reaction Conditions
entrya
catalyst (mol %)
Sc(OTf)3 (5)
DCP
yield (%)b
1
3
8
2
FeCl3 (5)
3
n.d.
21
n.d.
44
n.d.
74
45
21
78
43
41
68
24
3
InCl3 (5)
3
Table 2. Scope of the Reaction between Simple Alcohols and
N-Heterocycles
4
À
3
5
PdCl2 (5)
3
6
(rac)Binap (5)
PdCl2/(rac)Binap (5)
RhCl3/PPh3 (5/10)
PdCl2/(rac)Binap oxide (5)
PdCl2/(rac)Binap (5)
PdBr2/(rac)Binap (5)
PdCl2(PPh3)2
PdCl2/(rac)Binap (5)
À
3
7
3
8
3
9
3
10
11
12
13c
14c
3.5
3.5
3.5
3.5
3
a Conditions: 0.2 mmol of 1a, 1 mL of ethanol, catalyst, ligand, and
DCP at 120 °C in air for 10 h unlessotherwise noted. b NMR yield %. c 10
mol % HCl. n.d.: none detected. DCP: dicumyl peroxide.
We chose ethanol and lepidine asinitial substrates owing
to the ease of identification of the product (3a) and lack of
regioisomers formed. Interestingly, unlike our previous
work8 with cycloalkanes and N-heterocycles, we found
Sc(OTf)3 to be an inefficient catalyst for this reaction; 3a
could only be obtained in very low yields (Table 1, entry 1).
Other Lewis acids were tested; no product was detected
with FeCl3; however a slightly better yield was achieved
with InCl3. We were happy to find that the yield could be
increased to 44% with palladium dichloride (entry 5) and,
in the presence of (rac)Binap, 3a could be furnished in
74% yield (entry 7). Rhodium could also afford the
product, but at a lower yield (entry 8). A decreased yield
was obtained if (rac)Binap was replaced with (rac)Binap
oxide (entry 9). Increasing the amount of dicumyl peroxide
(DCP) in the system increased the conversion of the
starting material thereby increasing the yield (entry 10).
Other palladium catalysts were also tested (entries 11 and
12); however they were found to be inferior to the
PdCl2/(rac)Binap system. The reaction cannot be realized
in the presence of dicumyl peroxide alone or in the absence
of palladium (entries 4 and 6). As the Minisci reaction
requires stoichiometric amounts of acid, we wondered
whether a catalytic amount of HCl could improve the
yield. However, we found that the yield decreased slightly
upon addition of HCl (compare entries 10 and 13). More-
over, a control experiment was run using only 10 mol %
HCl and no palladium catalyst with only 24% of the
product obtained.
a Conditions: 0.2 mmol of heterocycle, 1 mL of alcohol, 5 mol %
PdCl2, 5 mol % (rac) Binap, 3.5 equiv of DCP at 120 °C in air for 16 h
unless otherwise noted. b Isolated yields. c At 135 °C with 3 equiv of DCP.
(8) (a) Deng, G.; Li, C.-J. Org. Lett. 2009, 11, 1171. For an account
on CDC reactions, see: (b) Li, C.-J. Acc. Chem. Res. 2009, 42, 335.
4582
Org. Lett., Vol. 13, No. 17, 2011

good yield (entry 6). These reaction conditions were found
to be ineffective for the addition of ethanol to quinazoline
(entry 8). Unfortunately the reaction scope is limited to
simple alcohols at this time. A small change in the reaction
conditions (higher temperature and decrease in amount of
peroxide) was found to be optimal for reaction with
propanol and butanol (entries 9À11).
reaction.3 Initiation of the reaction involves genera-
tion of the cumyl peroxide radical under heating. This
radical next abstracts the R hydrogen of the alcohol. The
nucleophilic carbon centered radical can add to the
N-heterocycle, and rearomatization of the hetero-
cycle is achieved through H-atom abstraction. We are
unsure of the role that palladium plays in this reaction;11
however it is possible that palladium may be participat-
ing in the generation or stabilization6b of the radical
intermediate.
In summary we have established a transition-metal-
catalyzed Minisci reaction. Unlike previous studies on
carbon centered radical additions to N-heterocycles,3,12
this reaction can be performed without the need for a
stoichiometric amount of acid. Further development of
this chemistry and expansion of the scope to different
alcohols are currently underway in our group.
Acknowledgment. We are grateful to the Canada Re-
search Chair (Tier I) Foundation (to C.J.L.), CFI, and
NSERC for their support of our research. C.A.C. would
also like to thank McGill University for the Max E. Binz
Fellowship.
Figure 2. (1) Reaction of isoquinoline N-oxide with ethanol. (2)
Reaction of isoquinoline with butryaldehyde.
To determine whether the peroxide was used as an
oxidant to create a highly reactive N-oxide in situ, isoquino-
line N-oxide was subjected to the reaction conditions.9 An
18% yield of 3a was obtained in the presence of DCP, and
no product was detected in the absence of peroxide. This
led us to eliminate N-oxide as an intermediate in this
reaction (Figure 2, eq 1). Similarly, we tested the possibility
of the peroxide oxidizing the alcohol to the aldehyde in situ
and the subsequent addition of the heterocycle to the
aldehyde. On reacting isoquinoline with n-butanal, 3l
was not detected, in either the presence or absence of
peroxide. However, ketone 5l was obtained in the presence
of peroxide (Figure 2, eq 2).
Supporting Information Available. Experimental detail
and characterization of all compounds. This material is
available free of charge via the Internet at http://pubs.acs.
org.
(10) Studer, A.; Curran, D. P. Angew. Chem., Int. Ed. 2011, 50
5018.
(11) Although HCl may be formed in situ from palladium-catalyzed
activation of the alcohol, we do not believe that this is the primary role of
the catalyst. In addition to the control experiment with 10 mol % HCl
(Table 1, entry 11), the reaction of lepidine and ethanol was also
performed in the presence of 10 mol % lepidine HCl but in the absence
3
of palladium dichloride; 35% of the product was obtained. Like the
traditional Minisci reaction, acids can catalyze the addition in low yields;
however we found that the metal catalyst system was needed to obtain
good yields.
(12) (a) Seiple, I. B.; Su, S.; Rodriguez, R. A.; Gianatassio, R.;
Fujiwara, Y.; Sobel, A. L.; Baran, P. S. J. Am. Chem. Soc. 2010, 13,
13194. For photochemical reactions, see: (b) Stermitz, F. R.; Wei, C. C.;
O’Donnell, C. M. J. Am. Chem. Soc. 1970, 92, 2745. (c) Castellano, A.;
Catteau, J. P.; Lablache-Combier, A.; Planckaert, B.; Alan, G. Chem.
Heterocycl. Compd. 1974, 10, 755 and references cited therein.
From these results we believe that the reaction proceeds
through a radical mechanism10 similar to the Minisci
(9) Deng, G. J.; Ueda, K.; Yanagisawa, S.; Itami, K.; Li, C.-J.
Chem.;Eur. J. 2009, 15, 333.
Org. Lett., Vol. 13, No. 17, 2011
4583