Iridium-catalyzed selective α-alkylation of unactivated amides with primary alcohols

Article abstract of DOI:10.1021/ol400360g

The first α-alkylation of unactivated amides with primary alcohols is described. An effective and robust iridium pincer complex has been developed for selective α-alkylation of tertiary and secondary acetamides involving a borrowing hydrogen methodology. The method is compatible with alcohols bearing various functional groups. This presents a convenient and environmentally benign protocol for α-alkylation of amides.

Full text of DOI:10.1021/ol400360g

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Iridium-Catalyzed Selective
r‑Alkylation of Unactivated Amides
with Primary Alcohols
Le Guo, Yinghua Liu, Wubing Yao, Xuebing Leng, and Zheng Huang*
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic
Chemistry, 345 Lingling Road, Shanghai 200032, China
huangzh@sioc.ac.cn
Received February 6, 2013
ABSTRACT
The first R-alkylation of unactivated amides with primary alcohols is described. An effective and robust iridium pincer complex has been
developed for selective R-alkylation of tertiary and secondary acetamides involving a “borrowing hydrogen” methodology. The method is
compatible with alcohols bearing various functional groups. This presents a convenient and environmentally benign protocol for R-alkylation of
amides.
The R-alkylation of amides is an important transforma-
tion for carbonÀcarbon bond formation and has found
widespread application in the synthesis of natural products
and biologically active compounds and in peptide modi-
fication.1 The uncatalyzed reaction of amide enolate with
alkyl halides is a traditional transformation for R-alkylation
of amides.1,2 However, this method suffers from the use of
mutagenic alkyl halides and the formation of waste salts. In
addition, prior to coupling, superbases (e.g., organolithium,
alkali metal amides) are required to generate thealkalimetal
enolate under very low temperature conditions.
halides, and their alkylation produces water as the only
waste product. In the past decade, alkylation with alcohols
employing the so-called “borrowing hydrogen” or “hydro-
gen autotransfer” methodology has emerged as a powerful
and green process for new bond formations.3 For example,
N-alkylation of amines,3f,h β-alkylation of alcohols,3b,c,g
alkylation of methyl-N-heteroaromatics,4 and R-alkyla-
tion of carbonyl and related compounds5 have been
achieved using primary alcohols as the alkylating reagents.
Recently, Ishii et al. reported a remarkable example of
R-alkylation of tert-butyl acetate with primary alcohols.6
The reaction occurred at 100 °C in the presence of
[Ir(COD)Cl]2 (10 mol % Ir), PPh3 (15 mol %), and KOtBu
(2 equiv) in tBuOH, giving the corresponding tert-butyl
esters in good yields. The substrate scope is limited to
tert-butyl acetate, and a large excess of this acetate (10
equiv) is required.6
In chemical and pharmaceutical industries, alcohols
are preferred alkylating reagents because they are less
expensive and more environmentally friendly than alkyl
(1) Challis, B. C.; Challis, J. In The Chemistry of Amides; Zabicky, J.,
Ed.; John Wiley & Sons: London, 1970; pp 731À857.
(2) For examples, see: (a) Kim, H.; Lee, H.; Lee, D.; Kim, S.; Kim, D.
J. Am. Chem. Soc. 2007, 129, 2269. (b) O’Donnell, M. J.; Zhou, C.; Scott,
W. L. J. Am. Chem. Soc. 1996, 118, 6070. (c) Seebach, D.; Beck, A. K.;
Bossler, H. G.; Gerber, C.; Ko, S. Y.; Murtiashaw, C. W.; Naef, R.;
Shoda, S.-I.; Thaler, A.; Krieger, M.; Wenger, R. Helv. Chim. Acta 1993,
76, 1564.
The aforementioned R-alkylation of carbonyl occurred
by an aldol reaction with aldehydes, which were derived
(4) (a) Blank, B.; Kempe, R. J. Am. Chem. Soc. 2010, 132, 924. (b)
Obora, Y.; Ogawa, S.; Yamamoto, N. J. Org. Chem. 2012, 77, 9429.
€
(3) For reviews, see: (a) Bahn, S.; Imm, S.; Neubert, L.; Zhang, M.;
€
(5) For examples, see: (a) Grigg, R.; Lofberg, C.; Whitney, S.;
Neumann, H.; Beller, M. ChemCatChem 2011, 3, 1853. (b) Suzuki, T.
Chem. Rev. 2011, 111, 1825. (c) Obora, Y.; Ishii, Y. Synlett 2011, 30. (d)
Saidi, O.; Williams, J. M. J. Iridium Catalysis 2011, 34, 77. (e) Watson,
A. J. A.; Williams, J. M. J. Science 2010, 329, 635. (f) Guillena, G.; J.
Ramon, D.; Yus, M. Chem. Rev. 2009, 110, 1611. (g) Dobereiner, G. E.;
Crabtree, R. H. Chem. Rev. 2009, 110, 681. (h) Fujita, K.; Yamaguchi,
R. Synlett 2005, 560.
Sridharan, V.; Keep, A.; Derrick, A. Tetrahedron 2009, 65, 849.
(b) Pridmore, S. J.; Williams, J. M. J. Tetrahedron Lett. 2008, 49,
7413. (c) Morita, M.; Obora, Y.; Ishii, Y. Chem. Commun. 2007, 2850.
(d) Taguchi, K.; Nakagawa, H.; Hirabayashi, T.; Sakaguchi, S.; Ishii, Y.
J. Am. Chem. Soc. 2003, 126, 72.
ꢀ
(6) Iuchi, Y.; Obora, Y.; Ishii, Y. J. Am. Chem. Soc. 2010, 132, 2536.
r
10.1021/ol400360g
XXXX American Chemical Society

R-alkylation of tertiary and secondary acetamides with
primary alcohols. This reaction provides a convenient and
environmentally benign route toa diverse libraryof amides
from very simple substrates.
Scheme 1. Synthesis of Complexes 1 and 2
The synthesis of the PN3P iridium complex 1 is outlined
in Scheme 1. Treatment of N,N-bis(di-tert-butylphosphino)-
2,6-diaminopyridine with 0.5 equiv of [Ir(COE)2Cl]2 in
toluene afforded complex 1 in 90% yield. The spectro-
scopic features of 1 show two broad signals for the NH
groups at9.13and 7.93ppm inthe 1H NMR spectrum. The
31P NMR spectrum of 1 exhibits an AB pattern at 100.7
and 90.0 ppm. The NMR data imply the formation of an
asymmetric cationic iridium PNP complex with an outer-
sphere chloride anion. The single-crystal X-ray structure of
1 confirms a pseudosquare coordination geometry of the
from primary alcohols via dehydrogenative activation.
Among carbonyl compounds, the R-hydrogens of amides
are the least acidic7 and therefore the aldol condensation
of amides with aldehydes itself has remained elusive.7a,8
Thus the R-alkylation of amides with alcohols is a signi-
ficant challenge. The few known examples of R-alkylation
of amides are limited to reactions of oxindoles9 and
4-hydroxy-quinolones10 containing activated R-CH. To
date, the R-alkylation of readily available unactivated
amides with primary alcohols has remained unknown.
Ir(I) site with the NH group participating in a NÀH Cl
3 3 3
hydrogen bonding interaction with the chloride anion (see
Figure 1). Complex 1 is air stable for at least several weeks
in the solid state and several days in solution.
The R-alkylation of N,N-dimethylacetamide 4a with
benzyl alcohol 3a employing complex 1 as the precatalyst
was selected as the model reaction. The reactions were
carried out under various conditions, and the results are
summarized in Table 1. Using 2 mol % 1, the reaction of 3a
(1 mmol) with 4a (2 mmol) in the presence of KOtBu
(1 equiv) in toluene (1 mL) at 120 °C gave the desired
product, N,N-dimethyl-3-phenylpropionamide 5a, in 62%
yield after 15 h (entry 1). The efficiency of this transforma-
tion increased with increasing amounts of KOtBu. The
reaction with 2 equiv of KOtBu provided an 88% yield of
5a (81% isolated yield),14 while decreasing the loading of
the base to 0.5 equiv gave 5a in 46% yield (entries 2 and 3).
Similarly, a high loading of KOtBu was also required in
the alkylation of tert-butyl acetate6 and methyl-N-hetero-
aromatics.4a The reactions in THF, 1,4-dioxane, digyme,
and DMF generated 5a, but in lower yields compared to
the reaction in toluene (entries 4À7 vs entry 2). The
reaction in neat N,N-dimethylacetamide (10 equiv relative
to 3a) gave the product 5a in 82% yield (entry 8). The
concentration of the reaction mixture has a minimal effect
on the productivity. Using the otherwise same reaction
conditions as those for entry 2, the reaction in a dilute
solution (15 mL toluene) afforded 5a in 81% yield (entry 9).
The efficiency of the reaction with NaOtBu (87%, entry 10)
is similar to the reaction efficiency with KOtBu, but using
KOH as the base gave the product 5a in a much lower yield
(25%, entry 11). No product was formed in reactions with
relatively weak bases such as Cs2CO3 and K2CO3 (entries
12 and 13).
Figure 1. ORTEP diagrams of complexes 1 (left) and 2 (right).
Since several iridium catalysts are known for dehydro-
genation of alcohols, we sought to develop a highly active
and robust iridium catalyst for R-alkylation of amides with
primary alcohols. Pincer iridium complexes exhibit high
thermal stability and are versatile in terms of alcohol,11
amine,12 and alkane dehydrogenation.13 Herein, we report
a new PN3P-type iridium pincer catalyst for the first
(7) pKa’s of amides, esters, aldehydes, and ketones in DMSO are ∼35,
∼31, ∼27, and ∼27, respectively; also see: (a) Foo, S. W.; Oishi, S.;
Saito, S. Tetrahedron Lett. 2012, 53, 5445. (b) Bordwell, F. G. Acc.
Chem. Res. 1988, 21, 456. (c) Fersner, A.; Karty, J. M.; Mo, Y. J. Org.
Chem. 2009, 74, 7245.
(8) For examples of aldol condensation of amides: (a) Ganesan, K.;
Brown, H. C. J. Org. Chem. 1994, 59, 7346. (b) Evans, D. A.; Tedrow,
J. S.; Shaw, J. T.; Downey, C. W. J. Am. Chem. Soc. 2001, 124, 392.
(9) (a) Jensen, T.; Madsen, R. J. Org. Chem. 2009, 74, 3990. (b) Grigg,
R.; Whitney, S.; Sridharan, V.; Keep, A.; Derrick, A. Tetrahedron 2009,
65, 4375.
We also evaluated the effectiveness of the known iridium
pincer complexes for R-alkylation of N,N-dimethylaceta-
mide 4a with benzyl alcohol 3a. With KOtBu (2 equiv) as
the base, the reaction in toluene using PONOP-Ir (6)
afforded the product 5a in 65% yield at 120 °C after 15 h
(entry 14), while using POCOP-Ir (7) and PCP-Ir (8)
(10) Grigg, R.; Whitney, S.; Sridharan, V.; Keep, A.; Derrick, A.
Tetrahedron 2009, 65, 7468.
ꢀ
(11) Morales-Morales, D.; Redon, R.; Wang, Z.; Lee, D. W.; Yung,
C.; Magnuson, K.; Jensen, C. M. Can. J. Chem. 2001, 79, 823.
(12) (a) Gu, X.-Q.; Chen, W.; Morales-Morales, D.; Jensen, C. M.
J. Mol. Catal. A: Chem. 2002, 189, 119. (b) Bernskoetter, W. H.;
Brookhart, M. Organometallics 2008, 27, 2036.
(13) For reviews, see: (a) Choi, J.; MacArthur, A. H. R.; Brookhart,
M.; Goldman, A. S. Chem. Rev. 2011, 111, 1761. (b) The Chemistry of
Pincer Compounds; Morales-Morales, D., Jensen, C., Eds.; Elsevier:
Amsterdam, 2007.
(14) Under otherwise identical conditions, the reaction using 1 equiv
of amide gave 5a in only 45% yield. Thus, all the reactions were
conducted with 2 equiv of amide.
B
Org. Lett., Vol. XX, No. XX, XXXX

Table 1. Iridium-Catalyzed R-Alkylation of N,N-Dimethylace-
tamide 4a with Benzyl Alcohol 3aa
Scheme 2. R-Alkylation of 4a with Various Primary Alcohols
(3bÀs)a
a Reaction conditions: iridium complex (0.02 mmol) in 1.0 mL of
solvent with 3a (1 mmol), 4a (2 mmol), and base (0.5À2 mmol) at 120 °C
for 15 h. b Yields were determined by 1H NMR with mesitylene as an
internal standard. Value in parentheses is isolated yield. c Using 15 mL of
toluene.
a Isolated yields. b Reaction performed with 3 equiv of KOtBu.
supported by anionic pincer ligands gave the product in
74% and 69% yields, respectively (entries 15 and 16). By
comparison, complex 1, PN3PÀIr, is most efficient (entry 2)
among the pincer Ir complexes for this transformation.
Complex 1 catalyzed R-alkylation of N,N-dimethylace-
tamide 4a with numerous primary alcohols was carried out
using the same reaction conditions as those for entry 2 in
Table 1. The results are summarized Scheme 2. The devel-
oped methodology worked efficiently for benzylic alcohols
bearing both electron-donating and -withdrawing groups.
Methyl and methoxy substitution in all the positions on
the aromatic ring was well tolerated, giving the alkylated
amides in 70À82% isolated yields (Scheme 2, 5bÀg). The
reaction of 4-chlorobenzyl alcohol with 4a gave 5h in 70%
isolated yield. Notably, 3-hydroxybenzyl alcohol (5i, 65%)
was compatible under the reaction conditions. The alkyla-
tion of 4a with 4-(methoxycarbonyl)benzyl alcohol occurred,
but it gave 4-[3-(dimethylamino)3-oxopropyl] benzoic acid
(5j, 62%) due to hydrolysis of the ester. Product 5j was also
obtained by the reaction of 4-carboxybenzyl alcohol with 4a,
albeit in relatively low yield (48%). Additionally, hetero-
cyclic alcohols, such as 2-furanmethanol (5k, 70%) and
2-pyridinemethanol (5l, 73%), underwent alkylation in
useful yields. Treatment of 2,6-pyridinedimethanol with
4a afforded 2,6-bis(N,N-dimethylpropionamide)pyridine
(5m, 53%),15 which is a potential liquidÀliquid extractant
for lanthanide and actinide metals.16 Alkylation of 4a with
3-phenyl-1-propanol and aliphatic alcohols such as cyclo-
hexylmethanol, n-butanol, and n-octanol gave the corre-
sponding N,N-dimethyl amides 5nÀq in 72À83% yields.
R-Alkylation of amide with alcohols bearing secondary
and tertiary β-carbons proceeded smoothly. The reactions
with 2-methyl-1-pentanol 4r and 2,2-dimethyl-1-propanol
4s gave the desired products 5r and 5s in 73 and 70%
isolated yields, respectively.
A range of N,N-disubstituted acetamides underwent
alkylation with a primary alcohol in high yields by this
method. The results are summarized Scheme 3. The reac-
tion of N,N-diethylacetamide with benzyl alcohol 3a gave
N,N-diethyl-3-phenylpropionamide (9b) in 78% isolated
yield. N-Acetylpiperidine was also efficiently alkylated with
benzyl alcohol (9c, 74%). Treatment of 4-acetylmorpholine
with 3a formed 4-(3-phenylpropanoyl)morpholine (9d) in
76% isolated yield.
(15) The single alkylation product, 3-(6-(hydroxymethyl)pyridin-2-
yl)-N,N-dimethylpropanamide, was also observed (15%).
(16) Binyamin, I.; Pailloux, S.; Duesler, E. N.; Paine, R. T.; Hay,
B. P.; Rapko, B. M. J. Heterocycl. Chem. 2007, 44, 99.
Org. Lett., Vol. XX, No. XX, XXXX
C

for R-alkylation of acetamides with alcohols, we prepared
a new Ir complex 2 (65%) by reaction of 1 with 1.5 equiv of
KOtBu (Scheme 1). The solid-state structure of 2 contains
an anionic PN3P ligand with no evidence for dearomatiza-
tion of the pyridine ring (Figure 1; see Supporting Infor-
mation for key bond distances and angles).17 Treatment of
complex 2 with KOtBu did not lead to further deprotona-
tion of the remaining NH group.
Scheme 3. R-Alkylation of Tertiary and Secondary Acetamides
(4bÀj) with Benzyl Alcohol Benzyl Alcohol 3aa
Using the isolated complex 2, the reaction of acetamide
4a with benzyl alcohol 3a in the presence of 2 equiv of
KOtBu at 120 °C afforded the alkylated product 5a in an
86% yield after 15 h. In addition, we tested the catalytic
activity of complexes 1 and 2 for the oxidation of benzyl
alcohol because the initial step in catalytic alkylation with
primary alcohols involves metal-catalyzed dehydrogena-
tion of alcohols to form aldehydes. With tert-butylethylene
as the hydrogen acceptor, the transfer dehydrogenation of
3a using 2 (1 mol %) did form 69% of benzaldehyde after
48 h at 120 °C, whereas the reaction using 1 (1 mol %) gave
a neglectable amount of benzaldehyde (<2%) under the
same reaction conditions (eq 1). Taken together, the data
indicate that complex 2 of the tridentate anionic PN3P
ligand is most likely to be the active catalytic species in the
R-alkylation of acetamides with alcohols. Related iridium
complexes of anionic bidentate PN ligands have been
reported by Kempe et al. for efficient N-alkylation of
amines.18
In summary, we report here an efficient method for the
first catalytic R-alkylations of unactivated acetamides with
primary alcohols. The simple preparation of the catalyst,
readily available and environmentally benign alkylating
reagents, formation of water as the only byproduct, and
tolerance toward many functional groups render this
method a highly attractive route for the R-alkylation of
tertiary and secondary amides.
a Isolated yields.
More importantly, this method was not limited to
reactions of tertiary amides; selective R-alkylation of sec-
ondary amides with alcohols occurred using this protocol.
Reactions of N-methyl acetamide, N-ethyl acetamide, and
N-tert-butyl acetamide with benzyl alcohol 3a selectively
formed the corresponding secondary amides 9eÀg in
72À80% isolated yields. R-Alkylation of N-aryl-substi-
tuted secondary amides including N-phenyl acetamide,
N-(4-methoxyphenyl) acetamide, and N-1-naphthalenyl
acetamide occurred to give the desired products 9hÀj in
63À80% isolated yields. Notably, no N-alkylation of
secondary amides with benzyl alcohol was observed in
these reactions. In contrast, R-alkylation of secondary
amides under basic conditions using alkyl halides as the
alkylating reagents often results in undesired N-alkylation.1
Having studied the substrate scopes of primary alcohols
and acetamides for the R-alkylation transformation, we
sought to determine the active species in catalysis. The
complex 1 contains two NH groups and may undergo de-
protonation in the presence of KOtBu. To assess whether a
deprotonated species derived from 1 is the active catalyst
Acknowledgment. We gratefully acknowledge financial
support from the National Natural Sciences Foundation
of China (Nos. 21272255, 21121062).
(17) In solution, however, the pyridine ring in 2 presumably under-
goes dearomatization according to H NMR analysis (see Supporting
Information). Also see: (a) Ben-Ari, E.; Leitus, G.; Shimon, L. J. W.;
Milstein, D. J. Am. Chem. Soc. 2006, 128, 15390. (b) He, L.-P.; Chen, T.;
Xue, D.-X.; Eddaoudi, M.; Huang, K.-W. J. Organomet. Chem. 2012,
700, 202.
Supporting Information Available. Experimental pro-
cedures and product characterization. X-ray crystallo-
graphic data (cif) for 1 and 2 are provided. This material is
available free of charge via the Internet at http://pubs.acs.org.
1
(18) (a) Michlik, S.; Hille, T.; Kempe, R. Adv. Synth. Catal. 2012, 354,
847. (b) Michlik, S.; Kempe, R. Chem.;Eur. J. 2010, 16, 13193.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX