Towa ds a gene al u henium-ca alyzed
hyd ogena ion o seconda y and e ia y amides o
amines†
Jose R. Cab e o-An onino,
a
Elisabe a Albe ico,
ab
Ka h in Junge,
a
Hen ik Junge
a
and Ma hias Belle *
a
A b oad ange o seconda y and e ia y amides has been hyd ogena ed o he co esponding
amines unde mild condi ions using an in si u ca alys gene a ed by combining [Ru(acac)
3
], 1,1,1-
is(diphenylphosphinome hyl)e hane (T iphos) and Yb(OT )
3
. The p esence o he me al ifla e allows o
mi iga e eac ion condi ions compa ed o p e ious epo s hus imp o ing yields and selec i i ies in he
desi ed amines. The excellen isola ed yields o wo scale-up expe imen s co obo a e he easibili y o
he eac ion p o ocol. Con ol expe imen s indica e ha , a e he ini ial educ ion o he amide ca bonyl
g oup, he eac ion p oceeds h ough he educ i e amina ion o he alcohol wi h he amine a ising om
collapse o he in e media e hemiaminal.
In oduc ion
Amines cons i u e an impo an class o compounds which ha e
wide indus ial applica ions as sol en s, addi i es, an i- oam
agen s, co osion inhibi o s, de e gen s, dyes, bac e icides.
1
In
addi ion, he amino g oup is abundan ly p esen in ag o-
chemicals and pha maceu icals.
1
Al hough alipha ic amines
can be p epa ed by nume ous me hodologies, educ i e ami-
na ions including alcohol amina ions p e ail in indus y on
la ge scale. In addi ion, p ima y a oma ic and benzylic amines
a e mos easily accessible by educ ion o he co esponding
ni oa enes and ni iles. Fo he p epa a ion o mo e s uc u -
ally complex bio-ac i e compounds and na u al p oduc s
a p e e ed ou e o C–N bond o ma ion combines amida ion
ollowed by educ ion.
2
This la e eac ion is usually accom-
plished by using (o e )s oichiome ic amoun s o li hium
aluminum hyd ide (LiAlH
4
) o bo ane (B
2
H
6
). Un o una ely,
hese eagen s equi e complex and haza dous wo k-up p oce-
du es and gene a e s oichiome ic amoun s o difficul o
dispose was e by-p oduc s. The e o e mo e efficien al e na i es
a e highly sough ae . Recen ly, me al-p omo ed ca aly ic
hyd osilyla ion o amides we e in ensely in es iga ed and mild
ope a ional condi ions ha e been de ised which allow o
excellen unc ional g oup ole ance, ye he me hod suffe s
om low a om efficiency because o esidual siloxanes.
3
Ano he
ecen example o a magnesium-ca alyzed deoxygena ion o
amides ia hyd obo a ion has simila limi a ions.
4
Ob iously,
he bes op ion o amide educ ion in e ms o a om economy
and was e p e en ion is hyd ogena ion wi h molecula
hyd ogen in he p esence o a sui able ca alys .
5
Howe e ,
because o he low elec ophilici y o hei ca bonyl g oup,
amides equi e ele a ed p essu es and empe a u es o be
educed. In he eld o he e ogeneous ca alysis, coppe –ch o-
mium oxide ca alys s o iginally de eloped o his aim ha e been
eplaced by less oxic, mo e efficien bi unc ional/bime allic
Ru/Mo,
6a
Rh/Mo,
6a,b
Ru/Re,
6a,c
and Rh/Re ca alys s
6a,c
and mo e
ecen ly by bime allic g aphi e-suppo ed Pd–Re
6d
and TiO
2
-
suppo ed P –Re based ca alys s.
6e,
Imp o emen o he e oge-
neous amide hyd ogena ion ca alys s has wi nessed a mi iga-
ion o eac ion condi ions, ye hey a e incompa ible wi h
a oma ic g oups and mul iple CC and CX bonds which a e
likewise educed. Despi e signican in e es in de eloping
homogeneous ca alys s which should ope a e unde milde
eac ion condi ions, no such gene al me hodology is a ailable.
In e es ingly, depending on he ype o homogeneous ca alys ,
he hyd ogena ion o amides affo ds ei he he alcohol and
amine, a ising om clea age o he C–N bond in he in e me-
dia e hemiaminal, o he mo e desi ed highe amine, esul ing
om deoxygena ion o he amide. The o me ype o selec i i y
is p e e en ially achie ed wi h bi unc ional ca alys s, which ely
on me al–ligand coope a ion, and can be ad an ageously
exploi ed as a mild dep o ec ion me hodology.
7
In es iga ions by Cole-Hamil on and co-wo ke s, la e sup-
po ed by con ibu ions om Lei ne 's and Klanke maye 's
g oups, ha e shown ha u henium ca alys s modied by 1,1,1-
is(diphenylphosphinome hyl)e hane (T iphos) gi e access o
a
Leibniz-Ins i u ¨
u Ka alyse e.V., Albe Eins ein S . 29a, 18059 Ros ock, Ge many.
E-mail: ma hias.belle[email p o ec ed]
b
Is i u o di Chimica Biomolecola e, Consiglio Nazionale delle Rice che, T . La C ucca
3, 07100 Sassa i, I aly
†Elec onic supplemen a y in o ma ion (ESI) a ailable: Gene al p ocedu es,
addi ional ables and schemes, cha ac e isa ion da a and NMR spec a o he
isola ed compounds a e a ailable. See DOI: 10.1039/c5sc04671h
Ci e his: Chem. Sci.,2016,7,3432
Recei ed 4 h Decembe 2015
Accep ed 8 h Feb ua y 2016
DOI: 10.1039/c5sc04671h
www. sc.o g/chemicalscience
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he highe amine (Scheme 1).
8
Ei he he ca aly ic sys em
gene a ed in si u om [Ru(acac)
3
] and T iphos
8a,b
o he eadily
accessible molecula ly dened complex [(T iphos)Ru(TMM)]
(TMM ¼ ime hyleneme hane)
8c
we e used o his ans-
o ma ion a high empe a u e. No ably, bo h sys ems equi e
he p esence o an acid co-ca alys such as me hanesul onic acid
(MSA)
8a–c
o bis( iuo ome hane)sul onimide (HNT
2
)
8d
and
he ca alys pe o mance is s ongly dependen on he acid/
u henium p ecu so a io. Al hough he indi idual in e medi-
a es a ound he ca aly ic cycle ha e so a escaped de ec ion, an
in-dep h s udy o he u henium species p esen in solu ion
unde ca aly ic condi ions has allowed o shed ligh on he ole
o he acid co-ca alys : i se es o con e he ca alys p ecu so
in o an ac i e sys em and i p o ides a weakly coo dina ing
coun e anion (CF
3
S(O)
2
O

o NT
2

) which, while s abilizing
he [Ru(T iphos)]
2+
agmen , does no p e en coo dina ion o
he incoming hyd ogen molecule and subs a e. Fu he mo e,
i p o ides he op imal eac ion medium pK
a
, o p omo e he
H- ans e and hyd oly ic e en s which make up amide
hyd ogena ion.
8c
The Ru–T iphos ca alys sys em is no ewo hy in ha , unlike
he e ogeneous ca alys s, i does no p omo e he hyd ogena ion
o a oma ic moie ies and, o he bes o ou knowledge, ep e-
sen s he only homogeneous ca aly ic sys em able o hyd oge-
na e amides o affo d he alkyla ed amine esul ing om he
hyd ogena ion o he ca bonyl g oup and he o mal hyd o-
genolysis o he ensuing C–OH bond. Howe e , ha sh condi-
ions a e s ill equi ed o achie e his ans o ma ion and he
subs a e scope is limi ed as he ca alys is bes sui ed o 1
amides and subs a es which bea a phenyl ing di ec ly
a ached o he ni ogen a om.
8
Recen ly, we ha e shown ha i is possible o ex end he
ange o a oma ic and alipha ic ca boxylic acids which can be
hyd ogena ed o he co esponding alcohols wi h he Ru–T i-
phos sys em by eplacing he B ¨
ons ed acid co-ca alys
8d,9
wi h
ei he Sn(OT )
2
o Al(OT )
3
,affo ding a milde and mo e gene al
me hod o he educ ion o hese challenging subs a es.
10a
The
Lewis acid is also key o he selec i e hyd ogena ion o es e s o
e he s p omo ed by he Ru–T iphos sys em: while no eac ion
occu s wi h me hanesul onic acid as co-ca alys , and poo
selec i i y is p o ided by iuo ome hanesul onic acid, he
combined use o Ru–T iphos and Al(OT )
3
gi es access o cyclic
and linea e he s in good o excellen yields.
10b
Inspi ed by hese esul s, we en isaged ha he p esence o
a sui able Lewis acid migh be c ucial o he educ ion o
amides as well, by ac i a ing he ca bonyl g oup and hus
allowing mi iga ion o he eac ion condi ions. He ein, we
p esen o he  s ime he esul s o ou de ailed in es iga-
ions which ha e led us o iden i y a supe io ca alys sys em o
he selec i e hyd ogena ion o a b oad ange o amides o
amines. Mo eo e , mechanis ic in es iga ions e ealed a no el
pa hway o he hyd ogena ion o amides.
Resul s and discussion
In o de o assess whe he a Lewis acid could indeed be
a benecial co-ca alys o he ans o ma ion unde in es iga-
ion, p elimina y expe imen s we e pe o med using he
hyd ogena ion o benzanilide 1as benchma k eac ion and he
me al ia es eadily a ailable in he labo a o y. The eac ions
we e un using he ca aly ic sys em gene a ed in si u om
[Ru(acac)
3
] and T iphos in THF a 150 C unde 50 ba o H
2
o
a s anda d eac ion ime o 15 hou s in he p esence o 1
equi alen o he Lewis acid as o u henium. The  s co-
ca alys s o be es ed we e Sn(OT )
2
and Al(OT )
3
as hese had
p o ed effec i e in co-ca alyzing he educ ion o ca boxylic
acids
10a
and he selec i e hyd ogena ion o es e s o e he s
espec i ely.
10b
While Sn(OT )
2
ga e poo con e sion wi h no
selec i i y in he desi ed N-benzylaniline 2, he only p oduc s
being benzyl alcohol 3and aniline 4(Table 1, en y 1),
11
Al(OT )
3
affo ded ull con e sion, al hough wi h a modes 27% selec i i y
(Table 1, en y 2). O he h ee me al ia es we e in es iga ed:
In(OT )
3
, Sc(OT )
3
, H (OT )
4
(Table 1, en ies 3, 4, 5). Essen ially
quan i a i e con e sions we e achie ed in all cases, wi h
H (OT )
4
p o iding he highes yield, 34%, o N-benzylaniline 2.
The use o a 2- old excess o he same Lewis acid as o Ru
allowed an inc ease in he yield o p oduc 2(42%, Table 1, en y
6) bu la ge amoun s we e de imen al (Table 1, en y 7 and 8).
Ha ing es ablished he op imal H (OT )
4
/Ru a io, his was
applied o p obe he inuence o empe a u e and p essu e on
selec i i y: he la e inc eases a highe empe a u e and lowe
p essu e (Table S1†), in line wi h p e ious ndings.
8a,c
The e o e
by educing he hyd ogen p essu e o 15 ba while keeping he
empe a u e a 150 C, he yield o N-benzylaniline 2 ose
u he o 63% (Table 1, en y 9). A con ol expe imen was un
in he p esence o iic acid (HOT ), as his migh a ise om
he hyd olysis o he co esponding me al sal (Table 1, en y
10): while a 84% con e sion was achie ed, hus sugges ing he
possibili y o a backg ound eac ion p omo ed by he B ¨
ons ed
acid, he selec i i y in 2was lowe (49%) han he one ob ained
wi h H (OT )
4
(63%), es ablishing he posi i e inuence o he
me al ion.
Scheme 1 Ru/T iphos ca aly ic sys ems compe en o he homoge-
neous hyd ogena ion o amides o amines.
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Unde he same expe imen al condi ions, almos no eac ion
ook place in he absence o he Lewis acid (Table 1, en y 11).
The esul s o his p elimina y su ey we e deemed encou -
aging and he sc eening o a wide ange o me al ia es
wo hwhile: he esul s a e summa ized in Fig. 1 and Table S2.†
T ia es o se e al ansi ion me als, o he hi d g oup
me als and o a ew o he a e-ea h ones, all p omo ed quan-
i a i e con e sion o benzanilide 1unde he applied condi-
ions. Howe e , he yield in N-benzylaniline 2was highly
affec ed by he ype o me al going om a minimum o 3% wi h
Mg(OT )
2
up o 74% wi h Yb(OT )
3
$H
2
O. Al(OT )
3
affo ded
a compa able yield, 72%, as o Yb(OT )
3
$H
2
O. Despi e he
sligh ly lowe cos o he o me ,
12
Yb(OT )
3
$H
2
O was selec ed as
he co-ca alys o choice in ligh o he posi i e cha ac e is ics
shown by a e-ea h me al ia es such as inc eased s abili y
owa ds mois u e and ai , compa ibili y wi h many Lewis bases
con aining ni ogen, oxygen, phospho us and sul u a oms
(which migh be benecial o unc ional g oup ole ance) and
he possibili y o being ecycled a he end o he eac ion, o
which hey a e ega ded as en i onmen ally iendly.
13
Finally,
none o he es ed B ¨
ons ed acids, me hanesul onic acid (MSA),
bis( iuo ome hane)sul onimide (HNT
2
) and he al eady
men ioned iic acid ou pe o med Yb(OT )
3
$H
2
O as co-ca a-
lys unde he same expe imen al condi ions.
Ha ing iden ied in Yb(OT )
3
$H
2
O he Lewis acid o choice,
mo e de ailed in es iga ions o he eac ion condi ions we e
ca ied ou .
Selec i i y in he amine 2 u ned ou o be affec ed by he
Yb(OT )
3
$H
2
O/ u henium a io and ei he less (Table 2, en y 1)
o mo e (Table 2, en y 3) han 2 (Table 2, en y 2) was de i-
men al. This a io was he e o e applied in all subsequen
expe imen s. When he amoun o ca alys was educed (Table
2, en y 4) ac i i y was e ained as con e sion was quan i a i e
bu selec i i y dec eased om 74% (Table 1, en y 2) o 68%. By
educing he hyd ogen p essu e u he om 15 o 5 ba he
yield o N-benzylaniline 2imp o ed om 74% (Table 2, en y 2)
o 85% (Table 2, en y 5). Ca ying ou he eac ion in he
p esence o molecula sie es o emo e wa e and shi he
equilib ium owa ds he desi ed amine did no affec con e -
sion bu had a d ama ic impac on selec i i y affo ding mo e
han 90% o benzyl alcohol 3and aniline 4(Table 2, en y 6).
Addi ion o a con olled amoun o wa e , 10% / as o he
amoun o he sol en THF, almos hal ed con e sion bu
affo ded he same selec i i y p o ided by anhyd ous condi ions
(Table 2, en y 7). The e o e he ad en i ious wa e p esen in
he sol en and ha p oduced by he eac ion i sel is equi ed
o op imal pe o mance, ei he none o mo e again is de i-
men al. When he eac ion was un in he absence o T iphos,
wi h (Table 2, en y 8) o wi hou Lewis acid (Table 2, en y 9),
con e sion was low and p oduc s a ising om hyd ogena ion o
he a oma ic ings we e obse ed, none o which was de ec ed
unde o he wise iden ical expe imen al condi ions, sugges ing
ha he eac ions a e indeed homogeneous. The p esence o
Yb(OT )
3
$H
2
O is essen ial o p omo e he eac ion unde such
mild condi ions, as no con e sion o benzamide 1a all is
obse ed wi h he sole Ru–T iphos ca alys (Table 2, en y 10). A
such low p essu e, eplacing he Lewis acid wi h an amoun o
iic acid equi alen o ha expec ed om i s comple e
hyd olysis educes con e sion om quan i a i e o 67% wi h an
e en mo e d ama ic impac on selec i i y in 2which d ops om
85 o 37% (Table 2, en y 11).
Table 1 Hyd ogena ion o benzanilide 1wi h he Ru/T iphos ca alys :
p elimina y explo a i e expe imen s in o sui able addi i es
En y
a
Addi i e (mol%) Con .
b
(%) 2
b
(%) 3
b
(%) 4
b
(%)
1 Sn(OT )
2
(2) 25 —25 25
2 Al(OT )
3
(2) >99 27 71 71
3 In(OT )
3
(2) 93 23 68 67
4 Sc(OT )
3
(2) >99 29 67 66
5 H (OT )
4
(2) >99 34 63 60
6 H (OT )
4
(4) >99 42 51 37
7 H (OT )
4
(6) >99 40 54 39
8 H (OT )
4
(10) 73 17 32 20
9
c
H (OT )
4
(4) >99 63 32 19
10
c
HOT (16) 84 41 39 26
11
c
—5—33
a
S anda d eac ion condi ions: benzanilide 1(100.6 mg, 0.5 mmol),
Ru(acac)
3
(2 mol%), T iphos (4 mol%), addi i e (2–16 mol%), THF
(2 mL) and H
2
(50 ba ) a 150 C, eac ion ime 15 h.
b
Con e sion o
1and yields o 2,3, and 4we e calcula ed by GC using hexadecane
as in e nal s anda d. In some cases, a iable amoun s o
N-phenylpy olidine (5–15%) we e p oduced ollowing acid p omo ed
ing-opening o THF.
c
Reac ions we e un unde 15 ba H
2
.
Fig. 1 Hyd ogena ion o benzanilide 1wi h he Ru/T iphos ca alys :
yield o amine 2in he p esence o diffe en Lewis and B ¨
ons ed acid
co-ca alys s. Reac ion condi ions: benzanilide 1(100.6 mg, 0.5 mmol),
Ru(acac)
3
(2 mol%), T iphos (4 mol%), addi i e (4 mol%), THF (2 mL) and
H
2
(15 ba ) a 150 C du ing 15 h. Yield o 2was calcula ed by GC using
hexadecane as in e nal s anda d.
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Conside ing he key ole o he Lewis acid, he possibili y
ha i migh be as well effec i e in combina ion wi h o he
Ru-ca alys p ecu so s was e alua ed: howe e , only bis(2-
me hylallyl)(1,5-cyclooc adiene) u henium(II) showed a simila
eac i i y, al hough wi h a sligh ly lowe selec i i y (Table S3†).
The s e ic and elec onic p ope ies o T iphos seem o be
peculia as none o he o he phosphines es ed in combina ion
wi h [Ru(acac)
3
] and Yb(OT )
3
$H
2
Oaffo ded a sys em ac i e o
amide educ ion (Table S4†).
Se e al sol en s o he han e ahyd o u ane we e sc eened
in o de o u he imp o e he efficiency o he [Ru(acac)
3
]/
T iphos/Yb(OT )
3
$H
2
O sys em (Table S5†). In gene al, e he -
based sol en s and alcohols, wi h some excep ions, p o ided
high con e sions, bu e he s affo ded be e selec i i ies. Wi h
isop opanol, e hylene glycol o 1,3-p opandiol he main by-
p oduc was he one a ising om sol en amina ion wi h
aniline 4. Bo h 2-me hyl- e ahyd o u ane and me hyl cyclo-
pen yl e he , which ha e been lis ed as g eene subs i u es o
THF,
14
p o ided in e io selec i i ies in he desi ed N-benzyla-
niline 2as o THF, which emained he sol en o choice o
u he es s.
The subs a e scope o he educ ion o se e al amides
using he [Ru(acac)
3
]/T iphos/Yb(OT )
3
$H
2
O sys em is epo ed
in Table 3: he eac ions we e un unde he op imised condi-
ions, in THF a 150 C and 5 ba H
2
o a s anda d eac ion ime
o 15 hou s. Fo poo ly eac ing subs a es, ei he he ela i e
amoun o ca alys was sligh ly inc eased o he eac ion ime
was ex ended, hus imp o ing bo h con e sions and selec i -
i ies in he desi ed amines. Highe boiling sol en s such as
dioxane o e hylene glycol die hyle he had o be used in such
cases, ins ead o THF, which ended o pa ly condense ou side
he glass ials inside he au ocla e o e p olonged eac ion
imes. In gene al, high con e sions we e ob ained, wi h a ew
excep ions, while yields in he desi ed amines we e mo e a i-
able, depending on he s uc u e o he amide. In any case, he
only by-p oduc s we e he alcohol and amine a ising om
hyd ogenolysis o he amide.
Ini ially, he hyd ogena ion o he bio- ele an p ima y
amide, nico inamide, was achie ed in mode a e yields (Table 3,
en y 1). Nex , selec ed benzamides we e es ed (Table 3, en ies
2–7) wi h p-benzanisidide (Table 3, en y 4) p o iding he
highes yield, 89%. In ag eemen wi h p e ious epo s,
8c
a phenyl subs i uen a ni ogen is benecial and bo h ac i i y
and selec i i y a e p og essi ely e oded going om N-phenyl o
N-benzyl o N–Me (Table 3, en ies 2, 6 and 7 espec i ely). Ve y
good yields a e ob ained ins ead wi h he anilides o ace ic
(Table 3, en y 9, 80%) and phenylace ic acid (Table 3, en y 8,
65%). Se e al a yl-subs i u ed ace anilides we e hen hyd oge-
na ed (Table 3, en ies 10–20): all ga e quan i a i e con e sions
and e y good o excellen yields wi h he sole excep ions o
3-chlo o- and 2-chlo o ace anilide, whose amine yields we e
49% and 30%, espec i ely. O e all, pa a-subs i u ed ace ani-
lides affo ded a highe yield han he co esponding me a- and
o ho-subs i u ed ones and no di ec co ela ion be ween he
elec onic na u e o he subs i uen s and amine yield became
e iden , al hough selec i i y seems qui e sensi i e o s e ics.
Seconda y amides con aining unc ional g oups such as es e
(me hyl-4-(phenylca bamoyl)benzoa e), ni o (40-ni o-
benzanilide) and alkenyl (N-phenyl ac ylamide) we e es ed
unde op imized condi ions affo ding low yields o he desi ed
amine due o selec i i y p oblems. In he case o subs a es
con aining wo amide g oups he selec i i y o he desi ed
Table 2 Hyd ogena ion o benzanilide 1wi h [Ru/T iphos/Yb(OT )
3
$H
2
O] sys em: fine uning o eac ion condi ions
En y
a
H
2
(ba ) [Ru] (mol%) [Yb] (mol%) Con .
b
(%) 2
b
(%) 3
b
(%) 4
b
(%)
1 15 2 2 >99 65 35 28
2 15 2 4 >99 74 24 15
3 15 2 6 >99 72 25 13
4 15 1 4 >99 68 33 24
5 5 2 4 >99 85 14 6
6
c
5 2 4 >99 5 90 94
7
d
5 2 4 59 2 54 57
8
e
52 4 44 ———
9
e
52 —32 ———
10 5 2 — — ———
11
52 —67 25 72 75
a
S anda d eac ion condi ions: benzanilide 1(100.6 mg, 0.5 mmol), Ru(acac)
3
(1–2 mol%), T iphos (2 eq. espec o Ru), Yb(OT )
3
$H
2
O(2–6 mol%),
THF (2 mL) and H
2
(5 o 15 ba ) a 150 C o e 15 h. In all eac ions he au ocla e was pu ged wi h 30 ba o hyd ogen o h ee imes. [Ru] ¼
[Ru(acac)
3
] and [Yb] ¼[Yb(OT )
3
$H
2
O] co espond o mol% o each species.
b
Con e sion o 1and yields o 2,3, and 4we e calcula ed by GC
using hexadecane as in e nal s anda d. In some cases, a iable amoun s o N-phenylpy olidine (5–10%) we e p oduced ollowing Yb(OT )
3
$H
2
O
p omo ed ing-opening o THF.
c
Run wi h molecula sie es (4 ˚
A).
d
Run wi h 0.2 mL o wa e .
e
Run wi hou T iphos. The only p oduc s
obse ed we e hyd ogena ion ing p oduc s.
Run in he p esence o HOT (12 mol%).
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Table 3 Subs a e scope in he hyd ogena ion o amides ca alyzed by [Ru(acac)
3
/T iphos/Yb(OT )
3
$H
2
O] sys em
En y
a
Amide 1a Con .
b
(%) Amine 2a 2a
b
(%) Sel.
b
(%)
169 11 14
2>99 85 [80] 85
380 40 50
4 >99 89 [79] 89
5>99 45 45
6
c
78 40 52
7
d
50 14 28
8
e
>99 65 65
9>99 80 80
10 >99 96 [82] 96
11
>99 59 59
12
g
>99 80 [70] 80
13
>99 49 49
14
g
>99 30 30
15 >99 90 90
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Table 3 (Con d. )
En y
a
Amide 1a Con .
b
(%) Amine 2a 2a
b
(%) Sel.
b
(%)
16 >99 89 [82] 88
17
h
>99 80 80
18 >99 95 [88] 95
19
i
>99 76 76
20 94 68 72
21 >99 [86] 100
22
d
95 [84] 100
23
i
>99 61 61
24
c
>99 76 76
25
c
>99 91 [85] 91
26
j
>99 80 [70] 100
27
c
>99 53 53
28
d
89 45 51
29
c
97 30 32
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diamine was poo ob aining mix u es o o e -alkyla ed amines.
The p esen p o ocol was highly effec i e o he educ ion o
dibenzo hiazepinone and dihyd odibenzoxazepinone, affo d-
ing he co esponding he e ocyclic amines in excellen isola ed
yields (Table 3, en ies 21 and 22, 86 and 84%, espec i ely).
Isoindoline was p oduced in 61% yield by hyd ogena ion o
oxindole (Table 3, en y 23, 61%): while con e sion was quan-
i a i e unde s anda d eac ion condi ions, a highe p essu e o
hyd ogen (50 ba ) was equi ed o maximise he selec i i y in
isoindoline a he expenses o 3H-indole, which is o he wise he
main by-p oduc . Se e al e ia y amides we e educed as well
(Table 3, en ies 24–30) gi ing access o N-subs i u ed he e o-
cycles in good (N-benzylmo pholine, 53%) o e y good yields
(N-e hyl- e ahyd oquinoline 91% and N-phenylpy olidine
80%). Al hough he yield o dime hyloc ylamine was modes
(Table 3, en y 30, 11%), he educ ion wi h a homogeneous
ca alys o he co esponding ully alipha ic e ia y amide,
a no o iously challenging subs a e, is he  s e e epo ed.
Al hough selec ed p oduc amines we e isola ed wi h mino
loss as o he GC yield, he easibili y o he syn he ic p o ocol
was u he demons a ed by g-scale eac ions o pa icula
subs a es. Indeed, N-e hyl-4-me hoxyaniline (Scheme 2, eqn (a))
and 10,11-dihyd o-5H-dibenzo[b,e]-[1,4]diazepine (Scheme 2,
eqn (b)) we e isola ed in 84 and 87% yield, espec i ely.
In e es ingly, du ing he assessmen o he [Ru(acac)
3
]/T i-
phos/Yb(OT )
3
$H
2
O sys em, i became clea ha he selec i i y in
N-benzylaniline 2 a ied o e ime inc easing a highe con e -
sions and ha benzyl alcohol 3and aniline 4we e essen ially he
only by-p oduc s in he educ ion o benzanilide 1.
Fig. 2 shows how he ela i e amoun s o he subs a e and he
a iousp oduc s a yo e imein hecou seo he eac ions
(Table S6†). To ou su p ise benzyl alcohol 3and aniline 4a e
he  s obse able p oduc s –in e media es –o benzanilide
educ ion. In he  s 2 hou s hei ela i e amoun s inc ease
pa allel o benzanilide con e sion, which is quan i a i e ae
5 hou s, while p oduc o ma ion con inues ae ha ime!
In e es ingly, ae eaching a maximum ae abou 3 h, he
concen a ions o benzyl alcohol 3and aniline 4d op as hey a e
consumed o affo d N-benzylaniline 2.
I appea s ha benzyl alcohol 3and aniline 4a e in e me-
dia es en ou e o he o ma ion o N-benzylaniline 2. They a ise
om collapse o he hemiaminal o med ae he ini ial
educ ion o he amide ca bonyl g oup. This is clea ly in
con as wi h he es ablished mechanis ic p oposal o he e o-
geneous o homogeneous amide educ ions. In o de o p o e
ou assump ion, a se ies o con ol expe imen s was ca ied ou
o shed ligh on he eac ion pa hway and he ole o he Lewis
acid. To begin wi h, a compe i i e expe imen unde he s an-
da d condi ions was ca ied ou by eac ing benzanilide 1wi h
3,5-dime hylbenzyl alcohol (Scheme S1†). As expec ed benza-
nilide was ully con e ed, bu 70% o he esul ing
Table 3 (Con d. )
En y
a
Amide 1a Con .
b
(%) Amine 2a 2a
b
(%) Sel.
b
(%)
30
d
31 11 36
a
S anda d eac ion condi ions: amide (0.5 mmol), Ru(acac)
3
(2 mol%), T iphos (4 mol%), Yb(OT )
3
$H
2
O (4 mol%), THF (2 mL) and H
2
(5 ba ) a 150
C, 15 h.
b
Con e sion o amide and yield o amine we e calcula ed by GC using hexadecane as in e nal s anda d. The isola ed yields, ae column
ch oma og aphy on silica gel, a e epo ed be ween b acke s. In all cases, only he alcohol and amine a ising om he C–N bond clea age in he
pa en amide we e de ec ed as by-p oduc s.
c
Reac ion condi ions: Ru(acac)
3
(6 mol%), T iphos (12 mol%), Yb(OT )
3
$H
2
O (12 mol%), 1,4-dioxane (2
mL), 60 h.
d
Reac ion condi ions: Ru(acac)
3
(6 mol%), T iphos (12 mol%), Yb(OT )
3
$H
2
O (12 mol%), THF (2 mL), 15 h.
e
Reac ion condi ions:
Ru(acac)
3
(4 mol%), T iphos (8 mol%), Yb(OT )
3
$H
2
O (8 mol%), 1,4-dioxane (2 mL), 60 h.
Reac ion condi ions: Ru(acac)
3
(6 mol%), T iphos (12
mol%), Yb(OT )
3
$H
2
O (12 mol%), 1,4-dioxane (2 mL), 45 h.
g
Reac ion condi ions: Ru(acac)
3
(4 mol%), T iphos (8 mol%), Yb(OT )
3
$H
2
O(8
mol%), THF (2 mL), 15 h.
h
Reac ion condi ions: Ru(acac)
3
(4 mol%), T iphos (8 mol%), Yb(OT )
3
$H
2
O (8 mol%), 1,4-dioxane (2 mL), 45 h.
i
Run a 50 ba o H
2
.
j
Reac ion condi ions: Ru(acac)
3
(6 mol%), T iphos (12 mol%), Yb(OT )
3
$H
2
O (12 mol%), e hylene glycol die hyle he (2
mL), 45 h.
Scheme 2 [Ru(acac)
3
/T iphos/Yb(OT )
3
$H
2
O] ca alyzed hyd ogena-
ion o amides: scale-up es s.
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N-subs i u ed aniline was he p oduc o alkyla ion by 3,5-
dime hylbenzyl alcohol. The p e e en ial eac ion wi h his
alcohol indica es ha educ ion o benzanilide is slow as
compa ed o he subsequen N-alkyla ion.
In ag eemen wi h ou p oposal, N-benzylaniline 2is
p epa ed in 90% yield om ei he he eac ion o benzyl alcohol
3(Scheme 3, eqn (1)) o benzaldehyde and aniline 4unde he
p e iously op imized hyd ogena ion condi ions (Scheme S2†).
As shown in Scheme 3 he syne gis ic combina ion o he
[Ru(acac)
3
]/T iphos ca alys and Yb(OT )
3
$H
2
O is needed o he
amine alkyla ion as no con e sion is obse ed o he wise
(Scheme 3, eqn (2) and (3)). I is no ewo hy ha e en wi hou
hyd ogen he eac ion be ween benzyl alcohol 3and aniline 4
p oceeded well o gi e N-benzylaniline 2in 70% (Scheme 3,
eqn (4)).
Examples ha e been epo ed in which me al ia es ca a-
lyze he di ec amina ion o simple allylic, p opa gylic and
benzylic alcohols h ough ca boca ion in e media es.
15
The e o e, he possibili y ha , in he absence o hyd ogen,
N-benzylaniline 2could be o med h ough di ec N-alkyla ion
o aniline 4wi h benzyl alcohol 3was aken in o accoun .
Howe e Yb(OT )
3
$H
2
O alone is no able o ca alyse his eac-
ion (Scheme 3, eqn (5)), nei he is he [Ru(acac)
3
]/T iphos
ca alys (Scheme 3, eqn (6)), hence bo h indi idual ca alys s a e
equi ed. Fu he mo e, he alkyla ion o aniline wi h 1-phenyl-
e hanol, a seconda y benzylic alcohol which easily gene a es he
s abilized ca boca ion, in he p esence o hyd ogen, p o ided
only a poo 12% yield o he alkyla ed amine (Scheme S3†).
Al hough in he absence o hyd ogen con e sion o he alcohol
was highe , he main p oduc hough (45% yield) was in his
case ace ophenone. Signican ly, con ol expe imen s we e un
using a p ima y alipha ic alcohol, 1-oc anol, unde iden ical
eac ion condi ions (Schemes S4 and S5†). In ac , N-oc ylani-
line was ob ained in 92% yield in he p esence o hyd ogen,
55% wi hou ! Again in his case he combina ion o he
[Ru(acac)
3
]/T iphos ca alys and Yb(OT)
3
$H
2
O is necessa y.
These esul s ule ou a simple ca boca ion mechanism. Alkyl-
a ion o aniline wi h benzyl alcohol is selec i e in ha he
p oduc o double alkyla ion was ne e obse ed, no e en when
N-benzylaniline was eac ed wi h ex a benzyl alcohol
(Scheme S7†).
The eac i i y pa e n o he alcohols, p ima y o seconda y,
benzylic o alipha ic, disp o es a di ec alkyla ion pa hway.
Ins ead, he con ol expe imen s in he absence o hyd ogen
indica e ha he [Ru(acac)
3
]/T iphos/Yb(OT )
3
$H
2
O sys em
shows ac i i y in he alkyla ion o aniline wi h an alcohol
16
which occu s h ough a bo owing hyd ogen pa hway.
17
The
la e comp ises he ini ial (i) oxida ion (dehyd ogena ion) o
he alcohol o o m he co esponding aldehyde h ough
hyd ogen ans e o he me al ca alys ,
18
(ii) condensa ion o
he aldehyde wi h he amine subs a e o gi e an imine in e -
media e, and (iii) educ ion o he imine by ans e o he
Fig. 2 Va ia ion o he subs a e con e sion and p oduc yields du ing
he hyd ogena ion o benzanilide 1wi h he Ru/T iphos/Yb(OT )
3
$H
2
O
ca aly ic sys em. Reac ion condi ions: benzanilide 1 (100.6 mg,
0.5 mmol), Ru(acac)
3
(2 mol%), T iphos (4 mol%), Yb(OT )
3
$H
2
O
(4 mol%), THF (2 mL) a 150 C, H
2
(15 ba , op g aph), (5 ba , bo om
g aph). Con e sion (X) o 1and yields o 2,3, and 4we e calcula ed by
GC using hexadecane as in e nal s anda d. Va iable amoun s o
N-phenylpy olidine (5–10%) we e p oduced ollowing Yb(OT )
3
$H
2
O
p omo ed ing-opening o THF.
Scheme 3 Con ol expe imen s showing he syne gic combina ion o
Ru(acac)
3
, T iphos and Yb(OT )
3
$H
2
O in p omo ing he alkyla ion
o aniline wi h benzyl alcohol ( ia hyd ogen bo owing in he absence
o hyd ogen).
a
Con e sion o 3and yields o p oduc 2we e calcu-
la ed by GC using hexadecane as in e nal s anda d.
b
Va iable amoun s
o N-phenylpy olidine (eqn (1) 7%, eqn (4) 4%, eqn (5) 6%) we e
p oduced ollowing Yb(OT )
3
$H
2
O p omo ed ing-opening o THF.
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hyd ogen e mini empo a ily s o ed in he ca alys . The poo
yields ob ained wi h seconda y alcohols eec s he in e io
eac i i y o ke ones as o aldehydes in he educ i e
amina ion.
19
Based on he expe imen s desc ibed abo e, a mechanism o
he o ma ion o amine 2 om amide 1is p oposed in Fig. 3. We
belie e ha amide hyd ogena ion unde he he e desc ibed
condi ions ini ially leads o hyd ogenolysis o he amide. Then,
a bo owing hyd ogen- ype alkyla ion o he amine wi h he
p oduced alcohol akes place. This new mechanis ic insigh
opens he doo o u he ca alys imp o emen s as well as new
ans o ma ions, e.g. he educ i e alkyla ion o amides as
shown in Scheme S1.†
Al hough nume ous u henium-based ca aly ic sys ems ha e
been de eloped o da e which p omo e he a om-economical
and en i onmen ally benign alkyla ion o amines wi h alcohols
(wa e is he only by-p oduc ), he p esen sys em is qui e
diffe en .
20,21
In ac , he esul s o ou con ol expe imen s, he
ecen ly epo ed Ru–T iphos ca alyzed amina ion o alcohols
wi h ammonia
22
and he me hyla ion o a oma ic amines wi h
o mic acid as he sole ca bon and hyd ogen sou ce
23
add o
he oolbox o use ul syn he ic ans o ma ion p omo ed by he
Ru–T iphos sys em o he syn hesis o amines, which includes
hei me hyla ion wi h H
2
and CO
2
( e . 24) and alkyla ion wi h
ca boxylic acids and hyd ogen.
25
I is clea ha he possibili y o achie e selec i e alkyla ion o
amines wi h an alcohol by combining he Ru/T iphos sys em
and Yb(OT )
3
$H
2
O, as highligh ed by he con ol expe imen s,
dese es u he in es iga ions as hese esul s ep esen he
 s examples o a eac ion o his ype which p oceeds unde
acid ca alysis and is cu en ly being explo ed in ou
labo a o ies.
Conclusions
The [Ru(acac)
3
]/T iphos ca aly ic sys em wi h Yb(OT )
3
cons i-
u es an imp o ed ca alys sys em o he hyd ogena ion o
alipha ic and a oma ic seconda y and e ia y amides.
Compa ed o p e ious wo k a signican ly b oade ange o
amides can be hyd ogena ed o he co esponding amines
unde milde condi ions. No special ca e is needed and he
eac ions can be simply se in ai . Con ol expe imen s indica e
adiffe en mechanism o his impo an ans o ma ion: ae
he ini ial educ ion o he amide ca bonyl g oup o he
hemiaminal his in e media e collapses o gi e he alcohol and
he non-alkyla ed amine. These compounds slowly p oduce he
desi ed p oduc ia a hyd ogen bo owing mechanism. The
syne gis ic combina ion o Ru/T iphos and he me al ia e is
necessa y o bo h s eps. Quan i a i e con e sions we e
achie ed wi h mos o he es ed subs a es while selec i i ies
s ill need o be imp o ed o some o hem. Fu he wo k is
aimed o allow o hyd ogena ion unde milde condi ions in
he p esence o mo e demanding unc ionalized subs a es, e.g.
pep ides. In he la e ins ance, because he only by-p oduc s
a e he alcohol and lowe amine, in es iga ions in o he
educ i e amina ion s ep migh se e o imp o e he sys em
u he on. Finally, i should be ecognized ha he [Ru(acac)
3
]/
T iphos/Yb(OT )
3
sys em is compe en o alcohol amina ion
h ough hyd ogen au o- ans e unde acidic condi ions.
Expe imen al de ails
Gene al p ocedu e o he hyd ogena ion o benzanilide (1)
A 8 mL glass ial con aining a s i ing ba was sequen ially
cha ged wi h benzanilide 1(100.6 mg, 0.5 mmol), Ru(acac)
3
(4.0 mg, 0.01 mmol), T iphos (12.5 mg, 0.02 mmol), Yb(OT )
3
-
$H
2
O (12.8 mg, 0.02 mmol), n-hexadecane (50 mg) as an in e nal
s anda d and THF (2 mL) as sol en . Ae wa ds, he eac ion
ial was capped wi h a sep um equipped wi h a sy inge needle
and se in he alloy pla e, which was hen placed in o a 300 mL
au ocla e. Once sealed, he au ocla e was pu ged h ee imes
wi h 30 ba o hyd ogen, hen p essu ized o 5–50 ba and
placed in o an aluminium block, which was p ehea ed a 130–
170 C. Ae he desi ed eac ion ime (0.5–25 h), he au ocla e
was cooled in an ice ba h, and he emaining gas was ca e ully
eleased. Finally, he eac ion mix u e was dilu ed wi h e hyl
ace a e and analysed by GC.
Acknowledgemen s
The au ho s would like o hank he ACS Pha maceu ical
Round able o nancial suppo and all i s membe s, especially
D Fab ice Gallou, Ma hew G is , Ca he ine Alde , Callie B yan,
Paul Richa dson, Dan Rich e and Emilie Pe e sen o ui ul
scien ic discussions. In addi ion, suppo by he s a e o
Mecklenbu g-Vo pomme n and he BMBF a e acknowledged.
J. R. C.-A. hanks he Ramon A eces Founda ion o a pos -
doc o al ellowship.
No es and e e ences
1(a) K. Elle , E. Henkes, R. Rossbache and H. Hoke, Ullman's
Encyclopedia o Indus ial Chemis y, Wiley-VCH, Weinheim,
2000, Amines, Alipha ic, DOI: 10.1002/14356007.a02_001;
(b)Amines: Syn hesis, P ope ies and Applica ions, ed. S. A.
Lawe ence, Camb idge Uni e si y, Camb idge, 2006.
2(a) J. S. Ca ey, D. Laffan, C. Thomson and M. T. Williams,
O g. Biomol. Chem., 2006, 4, 2337–2347; (b) S. D. Roughley
and A. M. Jo dan, J. Med. Chem., 2011, 54, 3451–3479.
3 Fo selec ed ecen examples, see: (a) S. Zhou, K. Junge,
D. Addis, S. Das and M. Belle , Angew. Chem., In . Ed.,
Fig. 3 P oposed mechanism o he o ma ion o he highe amine 2
om amide 1.
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