Catalytic acceptorless dehydrogenations: Ru-Macho catalyzed construction of amides and imines

Article abstract of DOI:10.1016/j.tet.2014.03.085

A commercially available ruthenium(II) PNP type pincer catalyst (Ru-Macho) promotes formation of amides and imines from alcohols and amines via an acceptorless dehydrogenation pathway. The formation of secondary amides, tertiary amides, and secondary ketimines occurs in yields ranging from 35% to 95%.

Full text of DOI:10.1016/j.tet.2014.03.085

Tetrahedron 70 (2014) 4213e4218
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Catalytic acceptorless dehydrogenations: Ru-Macho catalyzed
construction of amides and imines
*
*
Nathan J. Oldenhuis, Vy M. Dong , Zhibin Guan
Department of Chemistry, 1102 Natural Sciences II, University of California, Irvine, CA 92697-2025, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 5 March 2014
Received in revised form 24 March 2014
Accepted 25 March 2014
Available online 1 April 2014
A commercially available ruthenium(II) PNP type pincer catalyst (Ru-Macho) promotes formation of
amides and imines from alcohols and amines via an acceptorless dehydrogenation pathway. The for-
mation of secondary amides, tertiary amides, and secondary ketimines occurs in yields ranging from 35%
to 95%.
Ó 2014 Published by Elsevier Ltd.
Keywords:
Acceptorless dehydrogenation
Amide
Imine
Ruthenium catalysis
1. Introduction
O
O
Catalyst
Catalyst
R
OH
Amide bonds are prevalent in natural products, proteins, and
synthetic materials. The formation of amide linkages is one of the
most executed transformations in organic chemistry. Traditional
methods for amide bond formation often involve harsh conditions
and/or generate a stoichiometric amount of waste.1 With growing
environmental concerns, there is a need for more efficient, atom
economical, and environmentally friendly methods for amide
synthesis. As an indication, the formation of amide bonds via green
methods was named the number one challenge for organic
chemists by the ACS Green Chemistry Institute in 2007.2 To address
this challenge, a variety of new methodologies have emerged.1c
Among them, acceptorless catalytic dehydrogenation has received
particular attention for its ability to form amide bonds directly from
alcohols and amines3 (Scheme 1). Catalytic acceptorless dehydro-
genative amide synthesis circumvents the need for a stoichiometric
oxidizing agent or sacrificial hydrogen acceptor by evolving hy-
R"
R
N
R'
R
H
H
H
N
H2
H
H
R"
R'
Ligand Basic Site
This Work
(iPr)2P
PPh2
N
OC Ru
H
Et2N
N
N
Ru CO
Rh
H
PPh2
PPh2R
1
2
3
=
Scheme 1. Acceptorless dehydrogenation of an amine and alcohol to form an amide.
drogen gas directly from the reaction.4
A number of labo-
All catalysts shown contain a cooperative basic site on the ligand.
ratories3aed,5 have demonstrated promising catalysts for amide
bond formation via dehydrogenation using ruthenium catalysis.
Our group previously employed the Milstein catalyst (1) for the
synthesis of polyamides.6 Others have also applied acceptorless
dehydrogenation to the direct synthesis of esters,7 lactones,3b,7a
imines,5e,8 and pyrroles.3b,9 While searching for improved poly-
amidation catalysts, we discovered in this work that a commercially
available, relatively inexpensive catalyst (complex 3, Scheme 1)
catalyzed the synthesis of a variety of secondary and tertiary am-
ides, as well as secondary ketimines from alcohols and amines.
Given the potential of acceptorless dehydrogenation for amide
bond formation,10 we sought to identify inexpensive and robust
catalysts that could produce amide bonds. Previous studies dem-
onstrated that the catalytic cycle did not rely on redox chemistry at
the metal, but rather on metal/ligand cooperation.5c,11 In both the
€
Milstein catalyst (1) and the Grutzmacher catalyst (2), the catalytic
* Corresponding authors. E-mail addresses: dongv@uci.edu (V.M. Dong), zguan@
uci.edu (Z. Guan).
process was proposed to proceed through cooperative interactions
0040-4020/$ e see front matter Ó 2014 Published by Elsevier Ltd.
http://dx.doi.org/10.1016/j.tet.2014.03.085

4214
N.J. Oldenhuis et al. / Tetrahedron 70 (2014) 4213e4218
Table 1
of substrates with the basic site of the ligand and with the elec-
trophilic metal center utilizing catalysts based off the works of
Shvo, Murahashi, and others5f,12 (Scheme 1). A hydrogen acceptor is
not necessary because the ligands play an active role in the hy-
drogen abstraction and liberation process. The bulky ligands in
these catalysts, however, may hinder the ability of the substrate to
interact with both sites of the complex, which may explain why
tertiary amides are difficult to synthesize via reported acceptorless
dehydrogenation systems.3a,b,d,e,5d Of note, RueNHC complexes
have also emerged as promising catalysts.3def
Amide bond formation by acceptorless dehydrogenations of amines and alcohols
with Ru-Macho catalyst
1 mol% 4
H
R"
R
OH
+
+
N
2H2
R
N
R'
R"
R'
15 mol% KOH, 1.0 M
reflux, 12 h, toluene
nitrogen flow
Entry
Amine
Alcohol
Amide
Yield
[%]a
1
2
3
91%
95%
90%
The commercially available PNP type ruthenium(II) catalyst,
(RuHCl(CO)(HN(CH2CH2PPh2)2)) pioneered by the Saito group (Ru-
Macho, Scheme 1, complex 3) has recently been reported to effi-
ciently hydrogenate esters to form the corresponding alcohols.13 In
this context, hydrogenation and dehydrogenation are reversible
reactions, we hypothesized that this industrially relevant catalyst
could be used for dehydrogenative amide formation. Complex 3 has
a number of desirable attributes for our purpose. Firstly, similar to
catalysts 1 and 2, complex 3 contains a basic site on the ligand to
provide the desired cooperative interactions between the substrate
and the metal/ligand framework (Scheme 1, complex 3). Secondly,
the ligand in complex 3 is less bulky than those in 1 and 2, which
may broaden the substrate scope relative to pincer type ligands.
Importantly, the precursor of complex 3 is commercially available
and relatively inexpensive. Lastly, it has previously demonstrated
robust catalytic activity in ethyl acetate formation from ethanol7b as
well as methanol water reformation,14 and is used in large scale
industrial applications.13a
4
5
6
92%
95%
79%
7
8
88%
88%
2. Results and discussion
First, we investigated the feasibility of direct amidation by
complex 3, by using 2-methoxyethanol and benzylamine as model
substrates (see SI, Fig. S1). A number of experimental parameters,
including the base, solvent, and H2 removal were varied. To form
the catalytically active complex 3, the pre-catalyst 4 must be acti-
vated with a base (Scheme 2). Initial attempts using NaOEt or
NaOtBu as the base resulted in no amide formation. Upon changing
to sodium hydroxide as the base, however, amide bond formation
was observed. Because the base appeared to have an effect on direct
amidation, the base and counter-ion was further investigated.
Among all bases evaluated (LiOH, NaOH, KOH, Na2CO3, K2CO3,
NaOEt, and NaOtBu), potassium hydroxide afforded the highest
yield of the desired amide (see SI, Fig. S1). Using KOH as the base,
we investigated the solvent effect for this transformation. Among
the list of both polar and nonpolar solvents examined, toluene and
dioxane gave the highest yield (w66%). Because catalyst 3 can
catalyze hydrogenolysis of esters and amides with the H2 generated
during dehydrogenation, removal of H2 was necessary to prevent
the reverse transformation.13a Indeed, introducing continuous ni-
trogen flow through the reaction flask afforded almost quantitative
amide formation.
9
95%
89%
10
11
12
13
89%
86%
85%
14
15
55%b
35%c
Reaction conditions: 1 mmol amine, 1 mmol alcohol, 0.01 mmol 3, 0.15 mmol KOH,
1.0 mL toluene, 110 ꢀC, 12 h.
a
Isolated yields.
24 h.
24 h in 1 mL xylene.
b
c
Scheme 2. Activation of Ru-Macho precatalyst 4 with base to form the active catalyst 3.
yields, demonstrating the efficiency and versatility of complex 3 in
amide bond formation. Simple linear aliphatic alcohols coupled
efficiently (entries 1 and 2). Similarly, aliphatic alcohols with
With this protocol in hand (1 mol % complex 4, 15 mol % KOH,
reflux, toluene, nitrogen flow), several amines and alcohols were
examined as coupling partners for amide bond formation. A variety
of amides (Table 1, entries 1e15) were obtained in good to excellent
b-branching also produced amides in high yields (entry 3). Ether
and tertiary amine groups were well-tolerated in the amidation
process (entries 5 and 7). An aniline substrate, which is less

N.J. Oldenhuis et al. / Tetrahedron 70 (2014) 4213e4218
4215
nucleophilic than aliphatic amines, afforded amide in 79% yield
(entry 6). To test whether optically active amines were racemized
or not during the amidation, an optically pure amine was subjected
to the catalytic protocol. The optically pure amide was obtained in
high yield (entry 8), suggesting no significant racemization occurs
during the dehydrogenative coupling (see Experimental). After
successful amidation with a variety of mono-amines and mono-
alcohols, diamines (entry 9), and diols (entry 10) were coupled to
form diamides in high yields, suggesting the applicability of making
polyamides using complex 3.6
The ability of the secondary amines to undergo coupling stands
out (Table 1, entries 11e15) because previously reported accept-
orless dehydrogenation catalysts have limited conversion for
forming tertiary amides directly from secondary amines and alco-
hols3a,b,d,5d or require high catalyst loadings.3e Piperidine and
morpholine were both coupled in 89% and 86% yield, respectively
(entries 11 and 12). A linear secondary amine with moderate steric
bulk was coupled in very good yield (entry 13). Systematically in-
creasing steric bulk of the secondary amine resulted in decreasing
yield (entries 13e15). Nevertheless, a more sterically encumbered
secondary amine, dibenzylamine, underwent coupling with mod-
est yield (entry 15). This result suggests that further ligand tuning
may open the door to the direct synthesis of more sterically hin-
dered tertiary amides, which are very difficult to access.1c
the reduced products between 40 and 91%. Our results represent
the highest yielding examples of secondary alcohols and amines
undergoing dehydrogenative coupling to generate secondary keti-
mines. More sterically hindered and acyclic alcohols transformed to
the corresponding ketimines in moderate yields (entries 2e5).
The ability of complex 3 to form both amides and imines results
from the common hemiaminal intermediate generated after the
dehydrogenative coupling of the alcohol and the amine (Scheme 3).
Typically, the hemiaminal (5a) undergoes another de-
hydrogenation via complex 3 to create the amide product (5b).
However, if the R0 substituent on the hemiaminal is a moiety other
than a hydrogen atom, complex 3 is unable to undergo elimination
of an equivalence of dihydrogen. Thus, imine formation is favored
through dehydration in the case of secondary alcohols due to no
other competing pathway.
Scheme 3. Hemiaminal 5a can either form an amide (5b) or imine (5c) depending on
the identity of R0.
Acceptorless dehydrogenative catalysts have also been shown to
afford secondary aldimines from primary alcohols and amines.5e,8
However, synthesis of secondary ketimines via the acceptorless
hydrogenation pathway remains problematic.8a,c Considering that
complex 3 could couple secondary amines efficiently, we reasoned
that ketimine formation would be feasible. Using complex 3,
cyclohexanol and benzylamine were shown to undergo coupling to
generate secondary ketimines (Table 2, entry 1) in nearly quanti-
tative yields on the basis of GCeMS and 1H NMR analysis.15 Boro-
hydride reduction of the resulting imines leads to isolated yields for
3. Conclusions
The catalyst 3 (Ru-Macho) investigated here has shown utility
for both amide and imine bond formation through the acceptorless
dehydrogenation pathway. As an advance, we demonstrate good
reactivity with secondary amines for the synthesis of tertiary am-
ides and an improved synthesis of ketimines from secondary al-
cohols. The combination of commercial availability, relatively low
cost, and general substrate scope makes Ru-Macho an attractive
catalyst for amide and imine bond formation. Future studies will
focus on stereoselective variants and using these insights towards
the construction of polyamides.
Table 2
Imine bond formation via acceptorless dehydrogenations of amines and alcohols by
Ru-Macho catalyst
4. Experimental section
1 mol% 4
R"
R
OH
+
+
H2 , H2O
NH2
R
N
R"
15 mol% KOH, 1.0 M
reflux, 12 h, toluene
nitrogen flow
4.1. General considerations
R'
All reactions were set up under a nitrogen atmosphere in
a Vacuum Atmospheres Company Glove box. Reactions carried out
outside of the glove box were performed under a nitrogen atmo-
sphere using standard Schlenk techniques. Toluene was purchased
from Fischer Chemical and purged with argon for 2 h, then dried by
passing it through two columns of neutral alumina under argon
pressure. Dioxane, DMF, DMSO, chlorobenzene, xylene, and DMF
were purchased from Aldrich Chemical Co. or Fischer Chemical, and
purged with nitrogen for 30 min before use. Amines and alcohols
were purchased at reagent grade or higher purity from Aldrich
Chemical Co., or Fischer Chemical and purged with nitrogen for
30 min before use. [RuHCl(CO)(HN(CH2CH2PPh2)2)] (4) was pur-
chased from Strem Chemicals Inc. and used as received. KOH was
purchased from Fisher Chemical, ground with a mortar and pestle
in the glove box to a fine powder, and stored in the glove box.
Column chromatography was performed using silica gel (Dynamic
Entry
1
Amine
Alcohol
Imine
Yield [%]a
85%
2
3
51%
40%
4
5
80%
40%
Adsorbents Inc. Silica, C-18 32e63 m, 60 A) and eluted using applied
air pressure with the indicated solvent system. All compounds were
characterized by 1H NMR, 13C NMR, ESI-MS, and IR. NMR spectra
were obtained using a Bruker Cryo 500 instrument. All 1H NMR and
13C NMR are reported in parts per million relative to TMS
(0.00 ppm) unless otherwise noted. IR spectra were obtained using
a Thermo Scientific Nicolet iS5 iD5 ATR IR spectrometer. GCeMS
Reaction conditions: 1 mmol amine, 1 mmol alcohol, 0.01 mmol 3, 0.15 mmol KOH,
1.0 mL toluene, 110 ꢀC, 8e12 h.
a
Isolated yields of reduced amines obtained by reduction of imine to amine with
sodium borohydride.
(CI) was performed using
a GCT Premier Micromass MS

4216
N.J. Oldenhuis et al. / Tetrahedron 70 (2014) 4213e4218
Technologies mass spectrometer, coupled with a Waters 7890A gas
chromatograph. ESI MS was performed using an LCT Premier
Micromass MS Technologies mass spectrometer.
55.5 ppm. IR (film) 3003.1, 2917.6, 2849.0, 1679.8, 1511.8, 1246.1,
1110.9, 1033.5 cmꢁ1
.
4.2.7. N-Benzyl-2-(diethylamino)acetamide (Table 1, entry 7). Clear
oil (193 mg, 88% isolated yield).1H NMR (500 MHz, CDCl3)
7.71 (br, s,
4.2. General procedure, for examples in Table 1
d
1H), 7.35e7.62 (m, 5H), 4.75 (d, J¼6 Hz, 2H), 3.08 (s, 2H), 2.54 (q,
An oven dried 10 mL round bottom flask equipped with a stir bar
was brought into the glove box with a reflux condenser. The flask
was charged with [RuHCl(CO)(HN(CH2CH2PPh2)2)] (4) (6.0 mg,
0.01 mmol, 1 mol %), KOH (8.2 mg, 0.15 mmol, 15 mol %), toluene
(1.0 mL), an amine (1 mmol, 1.0 equiv), and an alcohol (1 mmol,
1.0 equiv) in that order. After all reagents have been added to the
flask, the reflux condenser was attached and secured with a Keck
clamp. The top of the condenser was sealed with a septum and the
whole apparatus was then removed from the glove box. Once
outside the glove box, the apparatus was equipped to nitrogen flow
by inserting an inlet needle supplying a positive pressure of ni-
trogen into the septum, and an outlet needle connected to an oil
bubbler. The reaction mixture was heated at reflux in a silicone oil
bath overnight (12 h), then allowed to cool to rt, and the conversion
determined by GCeMS (CI). The resulting residue was subjected to
flash chromatography with the indicated solvent system to obtain
the purified amide in the reported isolated yield.
J¼7.0 Hz, 4H), 0.99 (t, 6H, 7.0 Hz) ppm. 13C NMR (125 MHz, CDCl3)
d
172.1,138.6,128.7,127.6,127.4, 57.5, 48.8, 43.0,12.4ppm. Thephysical
data were identical in all respects to those previously reported.20
4.2.8. (R)-2-Methoxy-N-(1-phenylethyl)acetamide (Table 1, entry
25
8). Colorless solid (169 mg, 88%). [
NMR (500 MHz, CDCl3)
a]
þ109.9 (c 2.0, MeOH) 1H
D
d 7.52e7.24 (m, 5H), 6.85 (br, s, 1H), 5.18
(m, 1H), 3.91e3.83 (m, 2H), 3.41 (s, 3H), 1.52 (d, J¼7.5, 3H) ppm. 13
C
NMR (125 MHz, CDCl3)
d 168.4, 143.0, 128.8, 127.4, 126.1, 72.1, 59.1,
48.0, 21.9 ppm. The physical data were identical in all respects to
those previously reported.21
4.2.9. N,N0-(1,4-Phenylenebis(methylene))bis(2-methoxyacetamide)
(Table 1, entry 9). White solid (265 mg, 95% isolated yield). HRMS
(ESI/CH2Cl2) m/z calcd for C14H20N2O4Na (MþNa)þ: 303.1321,
Found: 303.1331. 1H NMR (500 MHz, DMSO-d6)
d
8.32 (t, J¼6.0 Hz,
1H), 7.19 (s, 4H), 4.25 (d, J¼6.0 Hz, 4H), 3.84 (s, 4H), 3.31 (s, J¼7.0 Hz,
6H) ppm. 13C NMR (125 MHz, DMSO-d6)
169.4, 138.5, 127.7, 72.0,
59.1, 41.9. IR (solid) 3029.1, 2939.7, 2831.2, 1650.8, 1532.0, 1197.4,
1109.3, 733.1 cmꢁ1
d
4.2.1. N-Benzyloctanamide (Table 1, entry 1). Clear colorless oil
(194 mg, 91% isolated yield). 1H NMR (500 MHz, CDCl3)
d
7.44e7.36
.
(m, 2H), 7.34 (m, 3H), 5.72 (br, s, 1H), 4.51 (d, J¼5.5 Hz, 2H), 2.27 (t,
J¼7.5 Hz, 2H), 1.72 (m, 2H), 1.36 (m, 8H), 0.94 (t, J¼7.5 Hz, 3H) ppm.
4.2.10. 2,20-((Oxybis(ethane-2,1-diyl))bis(oxy))bis(N-benzylaceta-
mide) (Table 1, entry 10). Clear colorless oil (360 mg, 90% isolated
yield). HRMS (ESI/CH2Cl2) m/z calcd for C22H28N2O5Na (MþNa)þ:
13C NMR (125 MHz, CDCl3)
d 173.0, 138.5, 128.7, 127.8, 127.5, 43.5,
36.8, 31.7, 29.3, 29.1, 25.8, 22.6, 14.1 ppm. The physical data were
identical in all respects to those previously reported.16
423.1896, found 423.1888. 1H NMR (500 MHz, CDCl3)
d 7.31e7.23
(m, 10H), 7.26 (br, s, 2H), 4.43 (d, J¼5.0 Hz, 4H), 3.92 (s, 4H), 3.50
(s, 8H). 13C NMR (125 MHz, CDCl3)
169.8, 138.2, 128.7, 127.8, 127.5,
70.8, 70.4, 70.0, 42.8. IR (film) 3030.1, 2913.0, 1656.8, 1529.8, 1496.5,
1454.0, 1102.6, 1028.5 cmꢁ1
4.2.2. N-Benzylbutyramide (Table 1, entry 2). White solid (168 mg,
d
95% isolated yield). 1H NMR (500 MHz, CDCl3)
d 7.35e7.26 (m, 5H),
6.60 (br, s, 1H), 4.45 (d, J¼7.5 Hz, 2H), 2.19 (t, J¼7 Hz, 2H), 1.69
.
(m, 2H), 0.96 (t, J¼7 Hz, 3H) ppm. 13C NMR (125 MHz, CDCl3)
d 173.1,
138.6, 128.7, 127.8, 127.4, 43.5, 38.6, 19.3, 13.9 ppm. The physical
4.2.11. 2-Methoxy-1-(piperidin-1-yl)ethan-1-one (Table 1, entry
11). Clear oil (135 mg, 86% isolated yield). HRMS (ESI/CH2Cl2) m/z
calcd for C8H15NO2Na (MþNa)þ:180.1001, Found: 180.0997. 1H NMR
data were identical in all respects to those previously reported.17
4.2.3. N-Benzyl-2-methylbutanamide (Table 1, entry 3). White solid
(500 MHz, CDCl3) d 4.10 (m, 2H), 3.55 (m, 2H), 3.42 (s, 3H), 3.39
(171 mg, 90%). 1H NMR (500 MHz, CDCl3)
d
7.34e7.26 (m, 5H), 5.83 (br,
(m, 2H), 1.65 (m, 2H), 1.57 (m, 4H). 13C NMR (125 MHz, CDCl3)
167.3, 59.0, 46.0, 42.9, 26.5, 25.6, 24.5. IR (film) 2926.3, 2854.6,
1644.6, 1466.0, 1117.7 cmꢁ1
s, 1H), 4.44 (m, 2H), 2.14 (m, 1H), 1.70 (m, 1H), 1.43 (m, 1H), 1.16 (d,
d
J¼5 Hz, 3H), 0.91 (t, J¼5 Hz 3H) ppm.13CNMR(125MHz, CDCl3)
d
176.4,
.
138.6, 128.7, 127.8, 127.4, 43.5, 43.3, 27.4, 17.6, 12.0 ppm. The physical
data were identical in all respects to those previously reported.18
4.2.12. Morpholino(phenyl)methanone (Table 1, entry 12). Clear oil
(164 mg, 86% isolated yield). 1H NMR (500 MHz, CDCl3)
7.42e7.39
(m, 5H), 3.75e3.45 (m, 8H) ppm. 13C NMR (125 MHz, CDCl3)
170.5,
d
4.2.4. N-Benzylbenzamide (Table 1, entry 4). White solid (194 mg,
d
92% isolated yield) (500 MHz, CDCl3)
d
7.80 (d, J¼7, 2H), 7.48
135.3, 129.9, 128.6, 127.1, 66.9 (2 carbons) ppm. The physical data
were identical in all respects to those previously reported.22
(m, 1H), 7.42 (t, J¼7 Hz, 2H), 7.36e7.28 (m, 5H), 6.48 (br, s, 1H), 4.65
(d, J¼5.5 Hz, 2H) ppm. 13C NMR (125 MHz, CDCl3)
d 167.4, 138.2,
134.4, 131.6, 128.9, 128.7, 128, 127.7, 127.0, 44.2 ppm. The physical
4.2.13. N-Benzyl-2-methoxy-N-methylacetamide (Table 1, entry
13). Clear oil (164 mg, 88% isolated yield). Due to constrained ro-
tational nature of the tertiary amide, the product is a mixture of two
rotamers (A: major, B: minor) in a 60:40 A:B ratio. NMR experi-
ments at 350 K showed coalescence of the two rotamer peaks. 1H
data were identical in all respects to those previously reported.19
4.2.5. N-Benzyl-2-methoxyacetamide (Table 1, entry 5). Clear col-
orless oil (170 mg, 95% isolated yield). 1H NMR (500 MHz, CDCl3)
d
7.36e7.26 (m, 5H), 6.82 (br, s, 1H), 4.49 (d, J¼10 Hz, 2H), 3.95 (s,
NMR (500 MHz, CDCl3) d 7.42e7.24 (m, 5H)[A][B], 4.65 (s, 2H)[A],
2H), 3.40 (s, 3H) ppm. 13C NMR (125 MHz, CDCl3)
d
169.5, 138.0,
4.58 (s, 2H)[B], 4.21 (s, 2H)[A], 4.20 (s, 2H)[B], 3.52 (s, 3H)[A], 3.48
128.8, 127.9, 127.6, 72.0, 59.2, 42.9 ppm. The physical data were
identical in all respects to those previously reported.18
(s, 3H)[B], 2.99 (s, 3H)[B], 2.94 (s, 3H)[A] ppm. 13C NMR (125 MHz,
CDCl3) d 169.4 [B], 169.1 [A], 137.0 [A], 136.3 [B], 129.0 [A], 128.7 [A],
128.2 [A], 127.8 [B], 127.5 [B], 126.6 [B], 71.6 [B], 71.5 [A], 59.3 [B],
59.2 [A], 52.5 [B], 51.0 [A], 33.7 [B], 33.64 [A] ppm. The physical data
were identical in all respects to those previously reported.23
4.2.6. 2-Methoxy-N-(4-methoxyphenyl)acetamide (Table 1, entry
6). Clear oil (154 mg, 79%). HRMS (ESI/CH2Cl2) m/z calcd for
C
10H13NO3Na (MþNa)þ: 218.0793, Found: 218.0797. 1H NMR
(500 MHz, CDCl3)
d
8.14 (br, s, 1H), 7.47 (d, J¼9.0 Hz, 2H), 6.87
4.2.14. N-Benzyl-N-ethyl-2-methoxyacetamide (Table 1, entry
14). White solid (113 mg, 55% isolated yield). Due to constrained
rotational nature of the tertiary amide, product is a mixture of two
(d, J¼9.0 Hz, 2H), 4.01 (s, 2H), 3.80 (s, 3H), 3.50 (s, 3H) ppm. 13C
NMR (125 MHz, CDCl3) d 167.3, 156.6, 130.3, 121.6, 114.2, 72.2, 59.3,

N.J. Oldenhuis et al. / Tetrahedron 70 (2014) 4213e4218
4217
rotamers (A: major, B: minor) in a 60:40 A:B ratio. NMR experi-
ments at 350 K in DMSO-d6 showed coalescence of the two rotamer
peaks. HRMS (ESI/CH2Cl2) m/z calcd for C12H17NO2Na
(MþNa)þ:230.1157. Found (MþNa)þ: 230.1148. 1H NMR (500 MHz,
(m, 5H), 3.74 (s, 2H), 2.41 (q, J¼6.0 Hz, 1H), 1.59 (s, 1H), 1.52e1.40
(m, 4H), 0.87 (t, J¼6.0 Hz, 6H) ppm. 13C NMR (125 MHz, CDCl3)
d
141.2, 128.7, 128.5, 127.1, 59.7, 51.5, 26.0, 10.2 ppm. The physical
data were identical in all respects to those previously reported.26
CDCl3)
d 7.36e7.22 (m, 5H)[A][B], 4.61 (s, 2H)[A], 4.52 (s, 2H)[B],
4.18 (s, 2H)[A], 4.11 (s, 2H)[B], 3.48 (s, 3H)[A], 3.42 (s, 2H)[B], 3.41
4.3.4. N-Benzyl-1-phenylethan-1-amine (Table 2, entry 4). Clear tan
(q, J¼6.5 Hz, 2H)[B], 3.25 (q, J¼6.5 Hz, 2H)[A], 1.14 (t, J¼6.5 Hz, 2H)
oil (168 mg, 80% isolated yield). 1H NMR (500 MHz, CDCl3)
[A], 1.11 (t, J¼6.5 Hz, 2H)[B]. 13C NMR (125 MHz, CDCl3)
d
169.0 [B],
d
7.48e7.22 (m, 10H), 3.85 (q, J¼6.5 Hz, 1H), 3.70 (d, J¼13.0 Hz, 1H),
169.0 [A],137.5 [A],136.8 [B],129.0 [A],128.6 [A],128.2 [A],127.7 [B],
127.4 [B], 126.6 [B], 71.7 [B], 71.4 [A], 59.3 [A], 59.3 [B], 49.7 [B], 47.7
[A], 40.9 [B], 40.6 [A], 13.7 [A], 12.6 [B] ppm. IR (film) 3033.1, 2924.2,
3.61 (d, J¼13.0 Hz, 1H), 1.70 (s, 1H), 1.39 (d, J¼6.5 Hz, 3H) ppm. 13
C
NMR (125 MHz, CDCl3)
d 145.6, 140.7, 128.6, 128.4, 128.2, 127.0,
126.9, 126.7, 57.5, 51.7, 24.5 ppm. The physical data were identical in
1644.0, 1452.0, 1431.9, 1134.8, 1109.4, 1080.5 cmꢁ1
.
all respects to those previously reported.25
4.2.15. N,N-Dibenzyl-2-methoxyacetamide (Table 1, entry 15). Clear
colorless oil (94 mg, 35% isolated yield). HRMS (ESI/CH2Cl2) m/z
calcd for C17H19NO2Na (MþNa)þ: 292.1313, Found: 292.1323. 1H
4.3.5. N-Benzyl-1,2,3,4-tetrahydronaphthalen-1-amine (Table 2, en-
try 5). Clear tan oil (94 mg, 40% isolated yield). 1H NMR (500 MHz,
CDCl3)
d
7.60e7.24 (m, 9H), 4.10 (d, J¼13.0 Hz, 1H), 4.00 (d,
NMR (500 MHz, CDCl3)
d
7.37e7.15 (m, 10H), 4.59 (s, 2H), 4.43 (s,
J¼13.0 Hz, 1H), 3.95 (t, J¼5.0 Hz, 1H), 3.04e2.84 (m, 2H), 2.24e2.04
(m, 3H), 1.94e1.85 (m, 1H), 1.54 (s, 1H) ppm. 13C NMR (125 MHz,
CDCl3) 142.2, 139.5, 137.7, 129.3, 129.0, 128.5, 128.3, 127.0, 126.8,
125.9, 54.9, 51.4, 29.6, 28.4, 19.3 ppm. The physical data were
identical in all respects to those previously reported.25
2H), 4.20 (s, 2H), 3.46 (s, 3H) ppm. 13C NMR (125 MHz, CDCl3)
169.5,136.9,136.1, 129.0,128.6,128.4, 127.7, 127.5, 126.6, 71.5, 59.3,
48.9, 47.9. IR (film) 3028.8, 2919.4, 1649.9, 1450.9, 1429.3, 1195.8,
1128.3, 1106.4, 1080.2 cmꢁ1
d
.
4.3. General procedure, for examples in Table 1
Acknowledgements
An oven dried 10 mL round bottom flask equipped with a stir bar
was brought into the glove box with a reflux condenser. The flask
was charged with [RuHCl(CO)(HN(CH2CH2PPh2)2)] (4) (6.0 mg,
0.01 mmol, 1 mol %), KOH (8.2 mg, 0.15 mmol, 15 mol %), and tol-
uene (1.0 mL), an amine (1 mmol, 1.0 equiv), and an alcohol
(1 mmol, 1.0 equiv) in that order. After all reagents had been added
to the flask, the reflux condenser was attached and secured with
a Keck clamp. The top of the condenser was sealed with a septum
and the whole apparatus was removed from the glove box. Once
outside the glove box, the apparatus was subjected to nitrogen flow
by inserting an inlet needle supplying a positive pressure of
nitrogen into the septum, and an outlet needle connected to an oil
bubbler. When the transformation was deemed complete on the
basis of analysis by GCeMS (CI), the reaction mixture was allowed
to cool to rt. 5 mL MeOH was added, and the resulting mixture was
stirred until the solution was homogeneous. NaBH4 (95 mg,
2.5 mmol, 2.5 equiv) was added through the top of the flask,
exposing the reaction to the atmosphere. The solution was stirred
for 1 h at rt. After 1 h, 3.5 mL 1 M HCl was added dropwise. The
solution was then diluted with 50 mL of EtOAc, washed with 1 M
KOH (3ꢂ50 mL), and finally brine (3ꢂ50 mL). The organic layer was
then dried with MgSO4 and the excess solvent was removed in
vacuo. The resulting residue was subjected to flash
chromatography.
Z.G. would like to thank the financial support received from the
US National Institutes of Health (DK098446) and the National Sci-
ence Foundation (CHE-1012422). V.M.D. would like to thank the
financial support received from the US National Institute of Health
(GM105938).
Supplementary data
These data include the substrate preparation, 1H NMR, and 13C
NMR spectra for all new compounds. Supplementary data related to
this article can be found at http://dx.doi.org/10.1016/
j.tet.2014.03.085.
References and notes
1. (a) Montalbetti, C. A. G. N.; Falque, V. Tetrahedron 2005, 61, 10827; (b) Valeur, E.;
Bradley, M. Chem. Soc. Rev. 2009, 38, 606; (c) Pattabiraman, V. R.; Bode, J. W.
Nature 2011, 480, 471.
2. Constable, D. J. C.; Dunn, P. J.; Hayler, J. D.; Humphrey, G. R.; Leazer, J. L.; Lin-
derman, R. J.; Lorenz, K.; Manley, J.; Pearlman, B. A.; Wells, A.; Zaks, A.; Zhang,
T. Y. Green Chem. 2007, 9, 411.
3. (a) Gunanathan, C.; Ben-David, Y.; Milstein, D. Science 2007, 317, 790; (b) Schley,
N. D.; Dobereiner, G. E.; Crabtree, R. H. Organometallics 2011, 30, 4174; (c)
Gnanaprakasam, B.; Milstein, D. J. Am. Chem. Soc. 2011, 133, 1682; (d) Nord-
strom, L. U.; Vogt, H.; Madsen, R. J. Am. Chem. Soc. 2008, 130, 17672; (e) Chen, C.;
Zhang, Y.; Hong, S. H. J. Org. Chem. 2011, 76, 10005; (f) Muthaiah, S.; Ghosh, S. C.;
Jee, J. E.; Chen, C.; Zhang, J.; Hong, S. H. J. Org. Chem. 2010, 75, 3002.
4. Gunanathan, C.; Milstein, D. Science 2013, 341, 249.
5. (a) Dam, J. H.; Osztrovszky, G.; Nordstrom, L. U.; Madsen, R. Chem.dEur. J. 2010,
16, 6820; (b) Shimizu, K.; Ohshima, K.; Satsuma, A. Chem.dEur. J. 2009, 15,
9977; (c) Zweifel, T.; Naubron, J. V.; Grutzmacher, H. Angew. Chem., Int. Ed. 2009,
48, 559; (d) Srimani, D.; Balaraman, E.; Hu, P.; Ben-David, Y.; Milstein, D. Adv.
Synth. Catal. 2013, 355, 2525; (e) Rigoli, J. W.; Moyer, S. A.; Pearce, S. D.;
Schomaker, J. M. Org. Biomol. Chem. 2012, 10, 1746; (f) Naota, T.; Murahashi, S. I.
Synlett 1991, 693.
4.3.1. N-Benzylcyclohexanamine (Table 2, entry 1). Clear tan oil
(158 mg, 85% isolated yield). 1H NMR (500 MHz, CDCl3)
d 7.32e7.19
(m, 5H), 3.81 (s, 2H), 1.93e1.89 (m, 2H), 1.75e1.70 (m, 2H),
1.65e1.59 (m, 1H), 1.44 (s, 1H), 1.33e1.00 (m, 6H) ppm. 13C NMR
(125 MHz, CDCl3)
d 140.9, 128.3, 127.9, 126.7, 56.1, 51.0, 33.5, 26.1,
24.9. The physical data were identical in all respects to those pre-
viously reported.24
6. Zeng, H. X.; Guan, Z. B. J. Am. Chem. Soc. 2011, 133, 1159.
7. (a) Zhang, J.; Leitus, G.; Ben-David, Y.; Milstein, D. J. Am. Chem. Soc. 2005, 127,
10840; (b) Nielsen, M.; Junge, H.; Kammer, A.; Beller, M. Angew. Chem., Int. Ed.
2012, 51, 5711; (c) Spasyuk, D.; Smith, S.; Gusev, D. G. Angew. Chem., Int. Ed.
2012, 51, 2772.
8. (a) Zhang, G. Q.; Hanson, S. K. Org. Lett. 2013, 15, 650; (b) Ho, H. A.; Manna, K.;
Sadow, A. D. Angew. Chem., Int. Ed. 2012, 51, 8607; (c) Gnanaprakasam, B.;
Zhang, J.; Milstein, D. Angew. Chem., Int. Ed. 2010, 49, 1468; (d) Maggi, A.;
Madsen, R. Organometallics 2012, 31, 451; (e) Esteruelas, M. A.; Honczek, N.;
Olivan, M.; Onate, E.; Valencia, M. Organometallics 2011, 30, 2468.
9. (a) Zhang, M.; Neumann, H.; Beller, M. Angew. Chem., Int. Ed. 2013, 52, 597; (b)
Michlik, S.; Kempe, R. Nat. Chem. 2013, 5, 140.
4.3.2. N-Benzyl-1,1-diphenylmethanamine (Table 2, entry 2). White
solid (139 mg, 85% isolated yield). 1H NMR (500 MHz, CDCl3)
d
7.49e7.22 (m, 15H), 4.88 (s, 1H), 3.78 (s, 2H), 1.89 (s, 1H) ppm. 13
C
NMR (125 MHz, CDCl3)
d 144.0, 140.5, 128.5, 128.5, 128.2, 127.4,
127.1, 127.0, 66.51, 51.9 ppm. The physical data were identical in all
respects to those previously reported.25
4.3.3. N-Benzylpentan-3-amine (Table 2, entry 3). Clear tan oil
10. Montag, M.; Zhang, J.; Milstein, D. J. Am. Chem. Soc. 2012, 134, 10325.
11. Yang, X. Z. ACS Catal. 2013, 3, 2684.
(71 mg, 40% isolated yield). 1H NMR (500 MHz, CDCl3)
d 7.37e7.20

4218
N.J. Oldenhuis et al. / Tetrahedron 70 (2014) 4213e4218
12. (a) Shvo, Y.; Blum, Y.; Reshef, D.; Menzin, M. J. Organomet. Chem. 1982, 226, C21;
(b) Murahashi, S. I.; Naota, T.; Ito, K.; Maeda, Y.; Taki, H. J. Org. Chem. 1987, 52,
4319; (c) Dobson, A.; Robinson, S. D. Inorg. Chem. 1977, 16, 137.
13. (a) Kuriyama, W.; Matsumoto, T.; Ogata, O.; Ino, Y.; Aoki, K.; Tanaka, S.; Ishida,
K.; Kobayashi, T.; Sayo, N.; Saito, T. Org. Process Res. Dev. 2011, 16, 166; (b) Ot-
suka, T.; Ishii, A.; Dub, P. A.; Ikariya, T. J. Am. Chem. Soc. 2013, 135, 9600.
14. Nielsen, M.; Alberico, E.; Baumann, W.; Drexler, H. J.; Junge, H.; Gladiali, S.;
Beller, M. Nature 2013, 495, 85.
18. Watson, A. J. A.; Maxwell, A. C.; Williams, J. M. J. Org. Lett. 2009, 11, 2667.
19. Moore, J. D.; Byrne, R. J.; Vedantham, P.; Flynn, D. L.; Hanson, P. R. Org. Lett.
2003, 5, 4241.
20. Shannon, S. K.; Peacock, M. J.; Kates, S. A.; Barany, G. J. Comb. Chem. 2003, 5,
860.
21. Ditrich, K. Synthesis 2008, 2283http://dx.doi.org/10.1055/S-2008-1078451
22. Ueda, T.; Konishi, H.; Manabe, K. Org. Lett. 2013, 15, 5370.
23. Stephenson, N. A.; Zhu, J.; Gellman, S. H.; Stahl, S. S. J. Am. Chem. Soc. 2009, 131,
10003.
24. Lee, O. Y.; Law, K. L.; Yang, D. Org. Lett. 2009, 11, 3302.
25. Eisenberger, P.; Bailey, A. M.; Crudden, C. M. J. Am. Chem. Soc. 2012, 134, 17384.
26. Carter, D. S.; Cai, H.-Y.; Lee, E. K.; Iyer, P. S.; Lucas, M. C.; Roetz, R.; Schoenfeld, R.
C.; Weikert, R. J. Bioorg. Med. Chem. Lett. 2010, 20, 3941.
15. Imine formation was monitored by GCeMS (CI) and 1H NMR analysis of the
reaction mixture. For ease of purification the imine was reduced with sodium
borohydride to the corresponding amine to prevent hydrolysis of the imine on
silica gel
16. Smith, S. M.; Thacker, N. C.; Takacs, J. M. J. Am. Chem. Soc. 2008, 130, 3734.
17. Chaysripongkul, S.; Pluempanupat, W.; Jang, D. O.; Chavasiri, W. Bull. Korean
Chem. Soc. 2009, 30, 2066.