N–Alkylation of Amines Catalyzed by a Ruthenium–Pincer Complex in the Presence of in situ Generated Sodium Alkoxide

Article abstract of DOI:10.1002/ejoc.201901310

We report the use of ruthenium–NNN-pincer complexes of the type (^R2NNN)RuCl₂(PPh₃) (R = tBu, iPr, Cy and Ph) for the catalytic N-alkylation of primary amines under solvent-free conditions. For the first time, the base that is required to promote these reactions is generated in situ from the alcohol by the use of sodium. The resulting sodium alkoxide regenerates the alcohol substrate while acting as the water scavenger thus mitigating the need of an additional base. Among the catalysts screened, (^tBu2NNN)RuCl₂(PPh₃) (0.02 mol-%) gives very high turnovers and good yields at 140 °C. The (^tBu2NNN)RuCl₂(PPh₃) catalyzed N-alkylation tolerates a variety of amine and alcohol substrates. While excellent turnover (29000) was obtained for the (^tBu2NNN)RuCl₂(PPh₃) (0.002 mol-%) catalyzed alkylation of aniline with cyclohexyl methanol, the turnovers obtained in the corresponding catalytic methylation of p-anisidine was also very high (12000). The (^tBu2NNN)RuCl₂(PPh₃) catalyzed reactions have also been accomplished under open-vessel conditions resulting in a net dehydrogenative coupling reaction. This protocol has been used to transform benzene-1,2-diamines to benzimidazoles with high productivity (12000 turnovers). DFT studies indicate that while β-hydride elimination is rate-determining (RDTS: 24.31 kcal/mol) for the alcohol dehydrogenation segment which is endothermic, insertion of the imine is rate-determining (RDTS: 11.26 kcal/mol) for its hydrogenation that is exothermic.

Full text of DOI:10.1002/ejoc.201901310

DOI: 10.1002/ejoc.201901310
Full Paper
Catalytic N-Alkylation
N–Alkylation of Amines Catalyzed by a Ruthenium–Pincer
Complex in the Presence of in situ Generated Sodium Alkoxide
Kanu Das,[a] Pran Gobinda Nandi,[a] Khadimul Islam,[a] Hemant Kumar Srivastava,*[a] and
Akshai Kumar*[a,b]
Abstract: We report the use of ruthenium–NNN-pincer com- ylation of aniline with cyclohexyl methanol, the turnovers ob-
plexes of the type (R2NNN)RuCl2(PPh3) (R = tBu, iPr, Cy and Ph) tained in the corresponding catalytic methylation of p-anisidine
for the catalytic N-alkylation of primary amines under solvent- was also very high (12000). The (tBu2NNN)RuCl2(PPh3) catalyzed
free conditions. For the first time, the base that is required to reactions have also been accomplished under open-vessel con-
promote these reactions is generated in situ from the alcohol ditions resulting in a net dehydrogenative coupling reaction.
by the use of sodium. The resulting sodium alkoxide regener- This protocol has been used to transform benzene-1,2-diamines
ates the alcohol substrate while acting as the water scavenger to benzimidazoles with high productivity (12000 turnovers).
thus mitigating the need of an additional base. Among the DFT studies indicate that while ꢀ-hydride elimination is rate-
catalysts screened, (tBu2NNN)RuCl2(PPh3) (0.02 mol-%) gives very determining (RDTS: 24.31 kcal/mol) for the alcohol dehydrogen-
high turnovers and good yields at 140 °C. The (tBu2NNN)RuCl2- ation segment which is endothermic, insertion of the imine is
(PPh3) catalyzed N-alkylation tolerates a variety of amine and rate-determining (RDTS: 11.26 kcal/mol) for its hydrogenation
alcohol substrates. While excellent turnover (29000) was ob- that is exothermic.
tained for the (tBu2NNN)RuCl2(PPh3) (0.002 mol-%) catalyzed alk-
Introduction
from the metal-dihydride leading to a net N-alkylated product
along with the regeneration of the dehydrogenation cata-
lyst.[3d–3f,4a–4e] Not all but a few catalytic systems require the use
of stoichiometric amounts of base or use of molecular sieves
to scavenge the by-product water (Scheme 1).[5] Use of base,
however, is likely to result in formation of additional by-prod-
ucts (Path A, Scheme 1).
N-alkylated amines are versatile intermediates that find wide
utility in the synthesis of fine chemicals, polymers, dyes and
pharmaceutical products.[1] Classical synthetic approaches to-
wards N-alkylated amines involve treatment of environmentally
toxic alkyl halide with amines.[2] As alkyl halides are obtained
either from alcohols or from olefins, it would be less hazardous
and more atom economical if one transforms either of these
precursors directly to the N-alkylated products. Accordingly, the
development of efficient synthetic routes to N-alkylated amines
in a “greener and atom economical” fashion remains a field of
immense interest.[3]
One of the most studied routes to N-alkylated amines in-
volves the use of alcohols as the alkyl precursor in transition
metal-catalyzed reactions (Scheme 1).[3d–3f,4] The first step
involves the metal-catalyzed dehydrogenation of the alcohol
giving rise to metal-dihydride and an aldehyde/ketone which
undergoes an uncatalyzed condensation followed by dehydra-
tion to give the corresponding imine (Scheme 1). The imine
then acts as a sacrificial acceptor and borrows the hydrogen
Scheme 1. Transition metal catalyzed N-alkylation using borrowing hydrogen
strategy.
[a] Department of Chemistry, Indian Institute of Technology Guwahati,
Guwahati – 781039, Assam, India
Williams coined the term “hydrogen borrowing” in his influ-
ential paper in 2004.[6] However, the concept of borrowing
hydrogen for the catalytic alkylation of amine was first imple-
mented independently by the groups of Grigg[7] and Wata-
nabe[8] in 1981. Driven by the extensive studies of van Koten,[9]
Milstein,[4e,10] Beller[3e,11] Corma,[4f,12] and Kempe[13] among oth-
ers, subsequent years saw the development of several catalytic
E-mail: hemantkrsri@gmail.com
akshaikumar@iitg.ac.in
http://www.iitg.ac.in/akshaikumar/Home.html
[b] Centre for Nanotechnology, Indian Institute of Technology Guwahati,
Guwahati – 781039, Assam, India
Supporting information and ORCID(s) from the author(s) for this article are
available on the WWW under https://doi.org/10.1002/ejoc.201901310.
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N-alkylation systems based on precious metals such as Pd,[14] be advantageous even if one avoids the possibility of formation
Ru,[4e,8–9,11b,15] Rh[7] and Ir.[13c,13d,16]
of one of these by-products. With this as one of the objectives,
the current study discusses the use of sodium metal to generate
the base (sodium alkoxide) in situ from the alcohol substrate
which is also the alkyl precursor for the (R2NNN)RuCl2(PPh3) (R =
However, recent years have witnessed a surge in the devel-
opment of catalytic systems based on inexpensive metals[5c]
such as Cu,[17] Mn,[5a,5b,18] Fe,[19] Ni[20] and Co.[13a,21] Emphasis
has also been laid on using heterogeneous catalytic N-alkyl-
ation systems based on Pd,[12b,14a,22] Au,[12a] Ag,[23] W,[24] Cu[25]
and Ni.[25,26] It is noteworthy that ruthenium-based N-alkylation
systems have enjoyed great success and have been reported
with several types such as [RuX2(PPh3)3] (X = Cl,[8,15e,15r–15t]
Br[15f]), [RuH2(PPh3)4],[15e] [RuHCl(PPh3)3],[15f] Ru–Phosphine
t
iPr, Bu, Cy and Ph) catalyzed N-alkylation (Scheme 1). Notably,
the by-product water is quenched by the sodium alkoxide re-
generating the alcohol substrate. Gratifyingly, in these ruth-
enium–pincer catalyzed solvent-free N-alkylation of amines with
sodium alkoxides, we observe very high turnovers (ca. 29000).
complexes,[15d,15f–15i,15m–15p,15x]
Ru-cyclopentadienyl
com-
Results and Discussion
Catalytic Activity of (R2NNN)RuCl2(PPh3) (R = iPr, tBu, Cy and
plexes,[27] Ru–amine complexes,[15j,15u] Ru–N-Heterocyclic com-
plexes[15d,15k] and even ruthenium–pincer complexes.[4e,9,15l,15q]
If the reaction shown in Scheme 1 is performed in an open- Ph) towards N-Alkylation of Amines. To arrive at the optimal
vessel, one would have H2 and H2O as by-products resulting reaction conditions, the 1a (0.02 mol-%) catalyzed reactions
in
a net dehydrogenative coupling reaction leading to were carried out at 120 °C in a sealed vessel using benzyl alco-
imines.[10,28] Using this approach, several heterocyclic com- hol (2) and aniline (3) as model substrates in the presence of
pounds[15n,15r,15t,19i,29] including quinolones,[15c,15q,18f,20b] pyrr- varying amounts of KOtBu (Entries 1–4, Table 1) for 20 h. For
oles[11a,11b,11d,15q,18h,30] and pyrimidines[13b,18g] of pharmaceuti- this variation, the best results (26 % yield, 1300 TON) (TON =
cal importance have been synthesized by Saito,[30b] Kirchner,[18f] [product]/[Catalyst]) were obtained with use of 0.75 equivalent
Milstein,[3d,4e,15l,28e,29c,29d,30a,30c]
Beller,[3e,11a,11b,11d] KOtBu (Entry 3, Table 1). Operating at a catalyst loading of
Kempe,[13b,18a,18g,18h] Kundu,[15c,29e] Balaraman[21c,30d,31] and Sri- 0.05 mol-% resulted in a higher yield albeit with lower turnover
mani.[29a,29b] For amine alkylation and dehydrogenative cou- (Entry 5, Table 1). Further increment in catalyst loading hardly
pling reaction, while phosphine-based ruthenium–pincer com- improved the yields (Entries 6 and 7, Table 1). Use of 0.75 equiv-
plexes continue to be in use by Milstein,[32] the applicability of alents of either K2CO3 or Et3N as the base in the (tBu2NNN)-
highly efficient Ru–NNN-pincers as attractive alternatives to air RuCl2(PPh3) (1a) (0.02 mol-%) catalyzed reactions did not yield
and moisture sensitive phosphine based complexes have been any products (Entries 8 and 10, Table 1). On the other hand,
independently demonstrated by Kundu,[15c] Hao[33] and presence of 0.75 equivalents of KOH resulted in very poor yield
Chen.[15q] Thus, the efforts to design catalytic systems based (Entry 9, Table 1).
on relatively expensive ruthenium that can demonstrate high
turnovers is still relevant and is being pursued worldwide with
great interest. Recently, we have demonstrated highly efficient
Kharasch addition reactions catalyzed by ruthenium–pincer
complexes of the type (R2NNN)RuCl2(PPh3) (1a; R = tBu, 1b; R =
Cy, 1c; R = iPr, and 1d; R = Ph).[34] A similar complex was re-
ported to be active for the transfer dehydrogenation of ket-
ones.[35] In this report, these complexes (Figure 1) have been
investigated towards solvent-free amine alkylation and de-
hydrogenative coupling with various alcohols.
To test the hypothesis of generating the base in situ (vide
supra), 0.75 equivalents of sodium was treated with benzyl alco-
hol 2 at 120 °C. To the resulting slurry (likely to be 2 and sodium
benzyloxide in the ratio 0.25:0.75) at room temperature, equiva-
lent amounts of aniline (3) containing 0.02 mol-% of 1a was
added and stirred at 120 °C in a sealed vessel. This reaction
resulted in better yields (53 %) and turnovers (2650) (Entry 11,
Table 1). Notably, under these conditions, the use of an addi-
tional base such as KOtBu is completely mitigated. In addition,
there is no possibility of formation of one of the by-products
Generally, under homogeneous conditions, either for N-Alkyl- (BH, path A, Scheme 1). These features make the current reac-
ation[18a,19f] or for dehydrogenative coupling,[13b] stoichiometric tion (entry 11, Table 1) more atom-economical in comparison
amounts of base such as KOtBu[13d,15j,15q,18a,18c,31,36] or with other reactions (entries 1–10, Table 1) and earlier re-
NaOtBu[18a,20b] are required. For N-Alkylation reactions, this ports.[18a,19f] Interestingly, the water formed in the reaction pro-
would generate an equivalent amount of metal salt and tert- motes the conversion of sodium benzyloxide back to 2 thus
butanol. While using molecular sieves[15j,15l,16l,19g] would be the maintaining its continuous supply in the catalytic cycle (path B,
best way to make this reaction more atom economical, it would Scheme 1).
Figure 1. Ruthenium–pincer catalysts investigated in the current study.
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Table 1. N-Benzylation of aniline catalyzed by (1a–d) under varying condi-
tions.
Table 2. Alkylation of various primary amines (1 equivalent) with benzyl alco-
hols (1 equivalent) catalyzed by (tBu2NNN)RuCl2(PPh3) (1a) (0.02 mol-%) in the
presence of 0.75 equivalent Na at 140 °C.
Entry
Additive
(X equiv.)
Ru–pincer
(Y mol-%)
Solvent
Yield[a]
%
TON
1
2
3
4
5
6
7
8
KOtBu (0.25)
KOtBu (0.50)
KOtBu (0.75)
KOtBu (1.00)
KOtBu (0.75)
KOtBu (0.75)
KOtBu (0.75)
K2CO3 (0.75)
KOH (0.75)
Et3N (0.75)
Na (0.75)
Na (0.75)
Na (0.75)
Na (0.75)
Na (0.75)
Na (0.75)
Na (0.75)
Na (0.75)
Na (1.00)
1a (0.02)
1a (0.02)
1a (0.02)
1a (0.02)
1a (0.05)
1a (0.1)
–
–
–
–
–
–
–
–
7
350
750
1300
800
920
450
260
0
15
26
16
46 1[b]
45
52
0
1a (0.2)
1a (0.02)
1a (0.02)
1a (0.02)
1a (0.02)
1a (0.02)
1a (0.02)
1a (0.02)
1a (0.02)
1a (0.02)
1a (0.02)
1a (0.1)
9
–
–
–
9
0
53
450
0
2650
10
11
12
13
14
15
16[e]
17[f]
18
19
20
21
22
23
24
Toluene
Benzene
THF
Dioxane
–
–
–
–
–
–
–
–
–
21 1[c](10)[d] 1050
17 (8)[d]
26 (2)[d]
28 (7)[d]
57
850
1300
1400
2850
800
730
470
2200
2200
1850
2650
600
16
73
47
44
44
37
1a (0.1)
Na (0.75)
Na (0.75)
Na (0.75)
NaOtBu (0.75)
NaOH (0.75)
1b (0.02)
1c (0.02)
1d (0.02)
1a (0.02)
1a (0.02)
53
12 (6)[d]
[a] Yield determined from 1H NMR using toluene as internal standard. [b]
Reported as an average of NMR and isolated yield. [c] Reported as an average
of NMR and GC yield. [d] Yield of the corresponding imine is given in paren-
thesis. [e] Reaction was performed at 140 °C. [f] Reaction was performed at
100 °C.
Under these optimized conditions, the introduction of sol-
vent gave reduced yields (entry 12–15, Table 1) of N-alkylated
product. Under solvent-free conditions, the yield of 1a cata-
lyzed N-alkylation could be improved (ca. 73 %) at higher cata-
lyst loading (Entry 18, Table 1) however at the cost of TONs.
The catalytic activity of other complexes 1b, 1c and 1d were
not on par when compared to that of 1a (Compare entries 20,
21 and 22 with entry 11, Table 1). As the catalytic system com-
prising of 0.02 mol-% 1a in combination with 0.75 equivalents
of sodium at 140 °C provided the best turnovers (ca. 2850) (En-
try 16, Table 1), similar conditions were used to check the reac-
tivity towards a variety of alcohols and amines (Table 2).
In the (tBu2NNN)RuCl2(PPh3) (1a) (0.02 mol-%) catalyzed N-
alkylation using benzyl alcohol, amines with electron-withdraw-
ing groups provided good but slightly lower TONs when com-
pared to use of aniline (compare TONs of product 4 with 4a
and with 4c, Table 2). On the other hand, amines with electron-
donating groups resulted in moderate turnovers (compare
TONs of product 4 with 4d and with 4e, Table 2). The turnovers
of 4 and 4a–e could be greatly enhanced by operating at lower
loading (0.002 mol-%) of 1a. Amines with sterically demanding
[a] Yield determined from 1H NMR using toluene as internal standard.
[b] Average of NMR and isolated yield. [c] Yield of the corresponding imine.
[d] Reaction performed for 48 h with 0.002 mol-% 1a. [e] Average of
NMR and isolated yield of two runs. [f] Reaction performed for 20 h with
0.2 mol-% 1a. [g] Reaction performed for 96 h with 0.002 mol-% 1a.
substituents and those with terminal double bonds were unre- formation of corresponding imines (4j, 4k, and 4l, Table 2).
active towards N-alkylation (4f and 4g, Table 2). Aliphatic Amines based on heterocyclic compounds gave moderate turn-
amines showed poor reactivity in general and mainly lead to overs (products 4h and 4i, Table 2) with 0.02 mol-% 1a which
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however improved upon lowering the catalyst loading to
0.002 mol-%.
Table 4. Alkylation of various primary amines (1 equivalent) with aliphatic
alcohols (4.8 equivalent) catalyzed by (tBu2NNN)RuCl2(PPh3) (1a) (0.02 mol-%)
in the presence of 1 equivalent Na at 140 °C.
For the (tBu2NNN)RuCl2(PPh3) (1a) (0.02 mol-%) catalyzed N-
alkylation of aniline, while electron-withdrawing groups on
benzyl alcohol (product 4m, Table 2) lowered the turnovers,
presence of electron-donating groups (product 4n, Table 2)
gave very high TONs. In particular, in the N-alkylation of aniline
with 4-methoxy benzyl alcohol, very high turnovers (ca. 17500)
could be obtained by operating at very low (0.002 mol-%) load-
ing of (tBu2NNN)RuCl2(PPh3) (1a). Moderate turnovers (products
4o and 4p, Table 2) were obtained when alcohols containing
heterocyclic substituents were used as an alkyl precursor. Under
the reaction conditions, cyclohexyl methanol provided excellent
turnovers (29000 TONs for 4r, Table 2) among the aliphatic alco-
hols used for the N-alkylation of aniline. The alkylation of repre-
sentative substrates with higher loading (0.2 mol-%) of 1a
showed an increase in yields (Table 2, footnote f, 4a, 4e, 4h,
4m, 4n, 4p, and 4r).
Catalytic Activity of (tBu2NNN)RuCl2(PPh3) (1a) Towards N-
Methylation of Amines. The use of methanol as a methylating
agent[15a,16i,16p,23b,37] presents an attractive strategy to generate
valuable N-methylated amines.[38] As the optimized conditions
given in Table 1 (Entry 16) gave poor yield of methylated aniline
(5, Table 2) the reaction parameters were further optimized for
use of methanol as the alkyl precursor (Table 3). While high
turnovers (ca. 1750, Entries 5 and 6, Table 3) were observed for
a combination of aniline and methanol in the ratio of 1:4.8 us-
ing 0.02 mol-% (tBu2NNN)RuCl2(PPh3) (1a), the yields could be
further improved (81 %, Entry 9, Table 3) upon increasing
the catalyst loading. The optimized condition (entry 6, Table 3)
that provided the best turnover was employed for the
[a] Yield determined from 1H NMR using toluene as internal standard. [b]
Reported as an average of NMR and isolated yield. [c] Reaction performed
for 48 h with 0.002 mol-% 1a. [d] Average of NMR and isolated yield of two
runs.
(
tBu2NNN)RuCl2(PPh3) (1a) catalyzed N-methylation of various
amines (Table 4).
uct 5 with 5a and with 5c, Table 4). However, when methylation
of 4-(trifluoromethyl) aniline was attempted, instead of the ex-
pected product 5b, 1698 turnovers of methyl-4-(dimethyl-
amino)benzoate (5bc) was obtained (Scheme 2) in addition to
trace amounts of 5ba and 5bb. Grinter[39] and Jones[40] have
independently demonstrated the hydrolysis of hydroxy-substi-
tuted and amino-substituted benzotrifluorides to the corre-
sponding benzoic acids. Accordingly, one could anticipate the
involvement of hydrolysis and subsequent esterification reac-
tions leading to the formation of 5ba (Scheme 2). Subsequent
methylation of 5ba could lead to product 5bc via 5bb.
The N-methylation reactions of amines with electron-donat-
ing groups, proceeded with higher TONs (compare TONs of
product 5 with 5d and with 5e, Table 4). Furthermore, the turn-
overs obtained in the N-methylation of p-anisidine could be
improved (12500 TONs of product 5d, Table 4) by operating at
very low loading (0.002 mol-%) of 1a. While the N-methylated
products 5f and 5g (Table 4) did not form, moderate TONs were
obtained in the 1a (0.02 mol-%) catalyzed N-alkylation of aniline
with ethanol and 2-propanol (products 5h–k, Table 4). Upon
lowering the loading of 1a (0.002 mol-%), excellent turnovers
were observed for the catalytic N-alkylation of aniline with
n-butanol and n-hexanol (products 5j and 5k, Table 4).
Table 3. Optimization of N-methylation of aniline catalyzed by (tBu2NNN)-
RuCl2(PPh3) (1a).
Entry
Sodium[a]
(X equiv.)
(1a)
(Y mol-%)
(3):MeOH
Yield[b]
TON
1
2
3
4
0.75
1.00
0.75
0.75
1.00
1.00
1.00
1.00
1.00
0.020
0.020
0.020
0.020
0.020
0.020
0.050
0.100
0.200
1.0:1.0
1.0:1.0
1.0:2.5
1.0:4.8
1.0:4.8
1.0:4.8
1.0:4.8
1.0:4.8
1.0:4.8
12
3
18
600
150
900
1100
1500
1750
1040
660
22 2[c]
30
5
6[d]
7[d]
8[d]
9[d]
35
52
66
81 2.6[e]
405
[a] Equivalent calculated with respect to aniline. [b] Yield determined from
1H NMR using toluene as internal standard. [c] Reported as an average of
NMR and GC yield. [d] Reaction was performed at 140 °C. [e] Reported as an
average of NMR and isolated yield.
The TONs obtained in the 1a (0.02 mol-%) catalyzed N-meth-
ylation of amines with electron-withdrawing groups were com-
Catalytic Activity of 1a Towards Dehydrogenative Cou-
parable to those obtained with aniline (compare TONs of prod- pling of Amines and Alcohols. As discussed earlier, exclusion
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Scheme 2. Anomalous product obtained in N-methylation of 4-(trifluoromethyl) aniline.
Table 5. Synthesis of benzimidazoles by dehydrogenative coupling of benzene-1,2-diamine with various primary alcohols catalyzed by (tBu2NNN)RuCl2(PPh3)
(1a).
Entry
Additive
(Equiv.)
(1a)
[mol-%]
R
Solvent
Yield[a]
%
TON
1
2
3
4
NaOtBu (0.001)
NaOtBu (0.75)
NaOtBu (0.75)
Na (0.001)
Na (0.25)
Na (0.005)
Na (0.001)
Na (0.001)
Na (0.001)
0.020
0.020
0.020
0.020
0.020
0.1
0.020
0.020
0.002
H
H
H
H
H
H
F
–
THF
Toluene
–
–
–
–
–
–
10 1[b]
Trace
Trace
32 2[b]
28
500
Trace
Trace
1600
1400
750
1700
2300
12000
5[c]
6
15
34
7
8
9
OMe
OMe
46 2[b]
24 1[b,d]
[a] Yield determined from 1H NMR using toluene as internal standard. [b] Reported as an average of NMR and isolated yield. [c] Reaction was performed at
200 °C. [d] Reaction was performed using 0.002 mol-% 1a.
of the hydrogenation segment in Scheme 1 would result in a carried out in the presence of 0.75 equivalents of sodium. If
net dehydrogenative coupling reaction. This approach has been path B was not involved, then complete deuterium incorpora-
utilized as a convenient tool for the synthesis of a variety of tion is expected in product 5. However, if path B is operative,
valuable heterocyclic compounds.[15n,15r,15t,19i,29] Accordingly, then in addition to the dehydrogenation of CD3OD to DCDO
we probed the reactivity of our catalytic systems towards de- and D2, one would expect the formation of CD3ONa and its
hydrogenative coupling of benzene-1,2-diamine with various subsequent reaction with H2O (formed by reaction of DCDO
primary alcohols (Table 5). The best results (ca. 1600 TONs, en- with 3) to generate CD3OH (Scheme 1). Further CD3OH upon
try 4, Table 5) towards the formation of benzimidazoles dehydrogenation would give HD and DCDO. The hydrogenation
were obtained with 0.02 mol-% 1a in the presence of only of imine 5′ with HD is likely to result in partial deuterium loss
0.1 mol-% of Na. As the reaction is performed at 140 °C under in the methyl group of 5. Alternatively, considering the fact that
open-vessel condition, water is effectively siphoned out making dehydrogenation of alcohol is endothermic with the equilib-
the need for stoichiometric amounts of base unnecessary. While rium more towards the left (see computational studies, vide
the turnover numbers of dehydrogenative coupling of benz- infra), the possibility of reverse reaction of HD with DCDO to
ene-1,2-diamine with benzyl alcohols with electron-withdraw- give CD3OH and CHD2OD cannot be ruled out. Similarly, reversi-
ing group was comparable, higher turnovers were obtained ble dehydrogenation of CHD2OD could further lead to stochas-
upon using benzyl alcohols with electron-donating group (en-
try 8, Table 5). The turnovers could be further enhanced (entry
9, Table 5) at lower loading (0.002 mol-%) of 1a.
Mechanistic Insights. To validate the hypothesis that the
base generated in situ (Scheme 1), reacts with the by-product
tic mixtures of HCDO, DCDO, HD, D2, CHD2OD, CD3OD, CH2DOD,
and CHD2OH. Over several cycles, due to the combined effect
of both forward and reverse reaction of hydrogen (labeled and
unlabelled) with imine 5′ and formaldehyde (labeled and unla-
belled) respectively, the deuterium content on the methyl
water while regenerating the alcohol, deuterium labeling exper- group on 5 is expected to be lowered. Accordingly, we observe
iments were performed. For this purpose, the reaction of a significant deuterium loss (ca. 75 %) in the methyl group
CD3OD with aniline catalyzed by (tBu2NNN)RuCl2(PPh3) (1a) was of 5.
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The complex 1b (0.01 mol-%) was found to catalyze the de- to correspond to an adduct of 4 with 1a (Figure 2). Rest to
hydrogenation of benzyl alcohol (2) at 150 °C under solvent- minor peaks could also be assigned to several derivatives of 1a
free conditions in an open vessel (Scheme 3). In this reaction, that presumably are involved in the catalytic cycle (Scheme 4).
about 245 turnovers of benzaldehyde (2′) and 25 turnovers of These observations form the basis of our mechanistic studies.
benzyl benzoate (26)[15l,41] were observed. Following a recent
literature procedure,[42] we were also able to detect hydrogen
using GC by withdrawing an aliquot of gas from the headspace
of this reaction mixture (Figure S65). Upon heating 2 with 3 in
the presence of 1a (0.02 mol-%) and NaOtBu (0.1 mol-%) at
140 °C under solvent-free conditions in an open vessel, 250
turnovers of imine 4′ was obtained. On the other hand, we
have already demonstrated that under sealed-vessel conditions
exclusive formation of 4 is observed (Table 1). Furthermore, re-
action of 4′ with H2 (4 atm) in the presence of 1a (0.2 mol-%)
and NaOtBu (1 mol-%) at 140 °C gave 4 in quantitative yield.
We also attempted to perform kinetic studies which are how-
ever not conclusive as obtaining meaningful and reproducible
kinetic data was challenging owing to the highly viscous nature
of the reaction mixture. However, plots depicting the changes
The plausible mechanism involved in the (R2NNN)RuCl2(PPh3)
(1a; R = tBu, 1b; R = Cy, 1c; R = iPr, and 1d; R = Ph) catalyzed
N-alkylation is depicted in Scheme 4 for aniline with benzyl
alcohol using 1c as a model catalyst. As shown in Scheme 4,
the precursor 8 is readily generated from salt metathesis of 1c
with the in situ generated base NaOCH2Ph. Loss of phosphine
from 8 would lead to the 16-electron complex 9. The 16-elec-
tron complex 9 is presumably the catalytically active species. A
similar 16-electron NNN–Ru species was shown to be active for
methanol dehydrogenation by Kundu and co-workers.[36] Very
recently, Yu and Li have also proposed the release of phosphine
and generation of CNP–Ru(II) species as the first step in the
dehydrogenation of benzyl alcohol.[43] The ꢀ-hydride elimina-
tion from the benzyloxide in complex 9 through TS 10 could
lead directly to the formation of 14 along with benzaldehyde
(2′) (purple dotted arrows, Scheme 4). Alternatively, a ꢀ-hydride
elimination via TS 11 could result in 12 where the benzalde-
hyde remains coordinated to the Ru center. Dissociation of
benzaldehyde from 12 can occur via TS 13 giving rise to 14.
Benzaldehyde (2′) undergoes an uncatalyzed condensation
with aniline 3 giving imine 4′.
1
in concentration (as determined by H NMR using toluene as
internal standard) of 2, 2′, 4′ and 4 with time for a variety of
reaction conditions in the 1a catalyzed alkylation of 3 have
been provided (Figures S66-S73). Figure S74 demonstrates the
increase in yield of 4 with catalyst loading.
HRMS (ESI) analysis of a 1a (10 mol-%) catalyzed the reaction
of 2 with 3 in the presence of 0.75 equivalents of NaOtBu at
Complex 14 could either react via path C (purple colored
140 °C after 3 hours indicated the major peak (m/z = 730.2165) arrows, Scheme 4) or via path D (magenta colored arrows,
Scheme 3. Control experiments performed to obtain preliminary mechanistic insight.
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Figure 2. HRMS (ESI) analysis of reaction mixture obtained from a 1a-catalyzed (10 mol-%) N-alkylation of aniline with benzyl alcohol at 140 °C after 3 hours.
Scheme 4. Plausible mechanism involved in the (R2NNN)RuCl2(PPh3)-catalyzed N-alkylation of amines. See Scheme S1 for the expanded version.
Scheme 4). Along path C, coordination of benzyl alcohol (2) to 4′ using H2 (Scheme 3). Along this path, the imine 4′ could
14 results in formation of 16 via TS 15. Subsequent σ-bond insert directly into the Ru–H bond in 14 via TS 20 resulting
metathesis in 16 between O–H and Ru–H going through TS 17 in the formation of 24. Another possibility would involve the
could give rise to η2-H2 complex 18. Dissociation of coordinated coordination of imine 4′ to Ru in 14 to give 22 via TS 21 (ma-
dihydrogen from 18 via TS 19 would regenerate the active com- genta dotted arrows, Scheme 4). Migratory insertion of the co-
plex 9. GC experiments (vide supra) provide conclusive evi- ordinated imine in 22[15b] results in the formation of 24 while
dence for the liberation of H2 (Figure S65). Under open-vessel going through TS 23. A σ-bond metathesis reaction of H2 and
conditions, only path C is likely to be operative with imine 4′ Ru–N in 24 via TS 25 regenerates 14 along with the formation
being the sole product. Accordingly, reaction of 2 and 3 cata- of N-alkylated product 4. Interestingly, derivative of species 12
lyzed by 1a (0.02 mol-%) in presence of NaOtBu (0.1 mol-%) at (m/z = 544.1747) and various derivatives of species 24 (m/z =
140 °C in an open-vessel provided 250 TONs of 4′ (Scheme 3).
Closed vessel conditions would result in the accumulation of
hydrogen which opens the possibility of path D which involves
655.0936, 696.1220, 730.2165) are observed in the HRMS (ESI)
analysis discussed vide supra.
Computational Studies. In order to attain insight into the
the reaction with H2. Independent experiments (vide supra) energetics of the 1c catalyzed N-alkylation, the various interme-
have been carried out to show the ability of 1a to hydrogenate diates and transition states (TSs) involved in the dehydrogen-
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Figure 3. Energy profile of various intermediates involved in the dehydrogenation segment of 1a-catalyzed N-alkylation of aniline with benzyl alcohol.
Figure 4. Energy profile of various intermediates involved in the hydrogenation segment of 1a-catalyzed N-alkylation of aniline with benzyl alcohol.
ation segment (Figure 3) and hydrogenation segment (Figure 4) Subsequent σ-bond metathesis in 16 between O–H and Ru–H
were modeled by DFT studies. Concerted ꢀ-hydride elimination to generate η2-H2 complex 18 is exothermic (–4.79 kcal/mol)
and release of benzaldehyde from 9 to generate 14 along TS and proceeds with a lower activation energy (TS: 17 ca.
10 (purple dotted arrows, Scheme 4) is endothermic (ca. 6.08 kcal/mol). The release of hydrogen from 18 to regenerate
9.32 kcal/mol) and requires high activation (purple dotted lines, 9 is also exothermic (–1.58 kcal/mol) with a very low barrier (TS:
Figure 3, ca. 34.19 kcal/mol). On the other hand, in a sequential 19 ca. 2.78 kcal/mol). The overall cycle catalyzed by 9 for the
reaction, the initial ꢀ-hydride elimination step (9→12) is endo- transformation of benzyl alcohol (2) to give benzaldehyde (2′)
thermic (ca. 22.56 kcal/mol) and has a lower barrier (TS 11; with the liberation of hydrogen is endothermic by 17.40 kcal/
ca. 24.31 kcal/mol). The subsequent step involving the dissocia- mol.
tion of benzaldehyde from 12 leading to 14 is exothermic
(–13.24 kcal/mol) and has a low energy of activation (TS 13; ca.
5.14 kcal/mol). Thus, the sequential ꢀ-hydride elimination and
benzaldehyde dissociation is clearly the favorable pathway (Fig-
ure 3). Furthermore, it is evident that the ꢀ-hydride elimination
(9→12) is the rate-determining step (RDS) (Figure 3).
In the hydrogenation segment, the step (14→24) involving
the concerted insertion of imine (4′) into the Ru–H appears to
be RDS (TS: 20 ca. 11.26 kcal/mol) and is exothermic (ca.
–1.36 kcal/mol) (Figure 4). The alternate path that involves the
initial coordination of the imine (4′) to 14 leading to 22 is endo-
thermic (ca. 10.14 kcal/mol) with a very high barrier (TS 21; ca.
The next step (14→16) involving the coordination of benzyl 30.55 kcal/mol). Thus, it is highly unlikely that this path (ma-
alcohol to the Ru in 14 is more endothermic (ca. 14.45 kcal/ genta dotted arrows, Scheme 4 and magenta dotted lines, Fig-
mol) with a relatively lower barrier of 21.35 kcal/mol (TS: 15). ure 4) will be followed although the subsequent migratory in-
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0.75 equivalents of sodium (0.087 g, 3.6 mmol) were added under
an argon atmosphere. The flask was closed and the contents were
stirred at 140 °C for about 2 hours with periodic venting of the
hydrogen that builds up during the process. The solution turned
clear when all the sodium had reacted. The mixture was cooled to
room temperature and to the resulting white slurry, aniline (3)
(0.47 mL, 5.14 mmol) and (tBu2NNN)Ru(Cl2)(PPh3) (1a) (0.7 mg,
1 μmol) were added in succession. The reaction mixture was heated
at 140 °C for 20 hours. The reaction was then cooled to room tem-
perature followed by addition of toluene (0.1 mL) as an internal
standard. An aliquot (30 mg) was withdrawn from the reaction mix-
ture and the yield was determined by 1H NMR using CDCl3 (0.5 mL)
as solvent. The rest of the reaction mixture was quenched with
water followed by extraction of organic fraction with dichloro-
methane. The organic phase was separated and was dried with an-
hydrous MgSO4 The solvent was removed from the organic fraction
under reduced pressure. Silica gel column chromatography using
hexane/ethyl acetate mixture (0 % - 5 %) as eluent gave product (4)
in the pure form. The isolated product was characterized by NMR
spectroscopy.
sertion in 22 to generate 24 is exothermic (ca. 11.5 kcal/mol)
with a very low barrier (TS 23; 4.09 kcal/mol). The regeneration
of 14 and release of the N-alkylated product (4) which involves
the σ-bond metathesis reaction of H2 and Ru–N is highly exo-
thermic (–22.88 kcal/mol) with a low barrier (TS: 25 ca.
8.49 kcal/mol). The overall 11 catalyzed hydrogenation of 4′ to
4 is exothermic (–24.24 kcal/mol).
Conclusions
Ruthenium–pincer complexes of the type (R2NNN)RuCl2(PPh3)
t
(1a; R = Bu, 1b; R = Cy, 1c; R = iPr, and 1d; R = Ph) have been
utilized to accomplish N-alkylation of primary amines. For the
first time, sodium is used in these reactions to generate the
required base in situ thus making the reaction more atom-
economical. Interestingly, water that is formed in the reaction
promotes the catalytic cycle by regenerating the alcohol precur-
sor from sodium alkoxide. Among the catalysts used,
(
tBu2NNN)RuCl2(PPh3) demonstrates the best activity towards
the solvent-free N-alkylation of various amines with a variety of
N-Benzylaniline (4):[15d] Yellow liquid; 1H NMR (400 MHz, CDCl3):
δ = 7.41–7.32 (m, 4H) 7.31–7.26 (m, 1H), 7.18 (td, J = 7.4, 1.9 Hz,
alcohols. In this study, while highest turnovers (29000) is ob- 2H), 6.72 (t, J = 7.3 Hz, 1H), 6.68–6.62 (m, 2H), 4.34 (s, 2H), 4.03 (s,
1H). 13C {1H} NMR (100 MHz, CDCl3): δ = 148.31, 139.59, 129.40,
tained for alkylation of aniline with cyclohexyl methanol, very
good results (12000 TONS) are also obtained for N-methylation
of p-anisidine. The work has been extended to the synthesis of
benzimidazoles with excellent turnovers (12000 TONs) under
solvent-free and open-vessel conditions via dehydrogenative
coupling of benzene-1,2-diamine with benzyl alcohols.
Quantum mechanical calculations performed to understand
the plausible reaction pathway indicates the dehydrogenation
of benzyl alcohol to be endothermic (ca. 17.40 kcal/mol) with
ꢀ-hydride elimination as the RDTS (ca. 24.31 kcal/mol). Notably,
sequential ꢀ-hydride elimination and benzaldehyde dissociation
are favored over a concerted pathway. On the other hand, the
imine hydrogenation is exothermic (ca. –24.24 kcal/mol) with
insertion of the imine 4′ into the Ru–H bond as the RDTS (ca.
11.26 kcal/mol). In case of hydrogenation, direct insertion of
imine into the Ru–H bond is preferred over sequential imine
coordination and subsequent migratory insertion.
128.77, 127.66, 127.37, 117.72, 113.00, 48.50. HRMS (ESI): [M + H]+,
Calculated 184.1126, found 184.1170.
1
N-Benzyl-4-fluoroaniline (4a):[3c] Yellow liquid; H NMR (400 MHz,
CDCl3): δ = 7.43–7.26 (m, 5H), 6.88 (t, J = 8.7 Hz, 2H), 6.61–6.53 (m,
2H), 4.30 (s, 2H), 3.93 (s, 1H). 13C{1H} NMR (151 MHz, CDCl3): δ =
156.00 (d, J1 C-F = 234.9 Hz), 144.61, 139.35, 128.80, 127.62, 127.44,
115.80 (d, J2 C-F = 22.3 Hz), 113.63 (d, J3 C-F = 7.4 Hz), 49.06. 19F{1H}
NMR (377 MHz, CDCl3): δ = –127.96. HRMS (ESI): [M + H]+, Calculated
202.1032, found 202.1048.
N-Benzyl-2,4,5-trifluoroaniline (4c):[45] Yellow solid; 1H NMR
(400 MHz, CDCl3): δ = 7.40–7.29 (m, 5H), 6.92–6.83 (m, 1H), 6.44 (dt,
J = 12.1, 7.9 Hz, 1H), 4.31 (d, J = 5.5 Hz, 2H), 4.24 (s, 1H). 13C{1H}
NMR (100 MHz, CDCl3): δ = 138.18, 128.99, 128.56, 127.94, 127.80,
127.47, 104.84 (t), 100.77 (dd), 48.21. 19F{1H} NMR (377 MHz, CDCl3):
δ = –138.71 (dd, J = 13.4, 2.6 Hz), –142.53 (dd, J = 22.1, 13.4 Hz),
–151.15 (dd, J = 22.2, 2.6 Hz). ESI-MS:[M + H]+, Calculated 238.0844,
found 238.0865.
N-Benzyl-4-methoxyaniline (4d):[15d] Yellow liquid; 1H NMR
(600 MHz, CDCl3): δ = 7.39–7.33 (m, 4H), 7.29–7.26 (m, 1H), 6.78 (d,
J = 8.9 Hz, 2H), 6.61 (d, J = 8.9 Hz, 2H), 4.29 (s, 2H), 3.75 (s, 3H).
13C{1H} NMR (151 MHz, CDCl3): δ = 152.29, 142.53, 139.77, 128.72,
127.68, 127.30, 115.01, 114.23, 55.92, 49.37. HRMS (ESI): [M + H]+,
Calculated 214.1232, found 214.1252.
N-Benzylcyclohexanimine (4j′):[28a] Yellow liquid; 1H NMR
(600 MHz, CDCl3): δ = 8.32 (s, 1H), 7.77–7.66 (m, 2H), 7.40 (dd, J =
4.0, 2.5 Hz, 3H), 3.19 (tt, J = 10.7, 4.2 Hz, 1H), 1.88–1.26 (m, 10H).
13C{1H} NMR (151 MHz, CDCl3): δ = 158.84, 136.69, 130.48, 128.67,
128.19, 70.21, 34.49, 25.77, 24.98. HRMS (ESI): [M + H]+, Calculated
188.1439, found 188.1457.
N-(4-Fluorobenzyl)aniline (4m):[16b] Yellow liquid; 1H NMR
(600 MHz, CDCl3): δ = 7.34 (dd, J = 8.3, 5.4 Hz, 2H), 7.22–7.15 (m,
2H), 7.03 (t, J = 8.7 Hz, 2H), 6.73 (t, J = 7.3 Hz, 1H), 6.66–6.60 (m,
2H), 4.30 (s, 2H), 4.03 (s, 1H). 13C{1H} NMR (151 MHz, CDCl3): δ =
162.17 (d, J1 C-F = 245.0 Hz), 148.05, 135.21 (d, J4 C-F = 3.2 Hz),
129.42, 129.13 (d, J3 C-F = 8.2 Hz), 117.87, 115.58 (d, J2 C-F=
21.3 Hz), 112.99, 47.85. 19F{1H} NMR (565 MHz, CDCl3): δ = –115.66.
HRMS (ESI): [M + H]+, Calculated 202.1032, found 202.1040.
Experimental Section
General: All manipulations were carried out under purified Ar using
a standard double manifold. All chemicals were purchased either
from MERCK or from Sigma Aldrich. While tetrahydrofuran (THF),
1,4-dioxane, toluene, and benzene were dried via double distillation
over Na/benzophenone prior to experiment, wherever required,
substrate alcohols and amines were purified according to a litera-
ture procedure.[44] The ruthenium–pincer complexes (1a–d) were
prepared following a literature protocol.[34]
Physical Measurements: 1H, 13C{H}, and 19F NMR were recorded
either on a Bruker ASCEND 600 operating at 600 MHz for 1H,
150 MHz for 13C and 564 MHz for 19F or on a Bruker AVANCE 400
operating 400 MHz for 1H, 100 MHz for 13C and 376 MHz for 19F.
HRMS measurements were done using an Agilent Accurate-Mass
Q-Toff ESI-MS 6520.
General Procedure for the Ruthenium–Pincer Catalyzed N-Alkyl-
ation of Amines with Alcohols: To a 5 mL high-pressure sealable
Schlenk flask containing benzyl alcohol (2) (0.53 mL, 5.09 mmol),
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N-(4-Methoxybenzyl)aniline (4n):[15d] Yellow liquid; 1H NMR
(600 MHz, CDCl3): δ = 7.36 (d, J = 8.6 Hz, 2H), 7.26 (t, J = 7.6 Hz,
J = 12.1, 8.0 Hz, 1H), 3.84 (s, 1H), 2.83 (d, J = 3.9 Hz, 3H. 13C{1H}
NMR (100 MHz, CDCl3): δ = 104.91, 104.89, 104.69, 104.67, 104.65,
2H), 7.00–6.92 (m, 2H), 6.83–6.77 (m, 1H), 6.75–6.67 (m, 2H), 4.31 (s, 104.44, 104.43, 100.00, 99.95, 99.76, 99.72, 30.55. 19F{1H} NMR
2H), 3.87 (s, 3H). 13C{1H} NMR (151 MHz, CDCl3): δ = 158.86, 148.25, (377 MHz, CDCl3): δ = –139.55 (dd, J = 13.6, 3.1 Hz), –142.84 (dd,
131.45, 129.31, 128.86, 117.52, 114.05, 112.88, 55.33, 47.80. HRMS J = 22.2, 13.4 Hz), –152.02 (dd, J = 22.3, 3.0 Hz).
(ESI): [M + H]+, Calculated 214.1232, found 214.1245.
4-Methoxy-N-methylaniline (5d):[15d] Yellow liquid; 1H NMR
N-(Furan-2-ylmethyl)aniline (4o):[15d] Yellow liquid; 1H NMR
(400 MHz, CDCl3): δ = 7.37 (s, 1H), 7.19 (t, J = 7.9 Hz, 2H), 6.75 (t,
J = 7.3 Hz, 1H), 6.68 (d, J = 7.8 Hz, 2H), 6.33 (dd, J = 3.0, 1.9 Hz, 1H),
6.24 (d, J = 2.9 Hz, 1H), 4.33 (s, 2H), 4.01 (s, 1H). 13C{1H} NMR
(100 MHz, CDCl3): δ = 152.86, 147.75, 142.06, 129.37, 118.16, 113.28,
110.46, 107.12, 41.57. HRMS (ESI): [M + H]+, Calculated 174.0919,
found 174.0934.
N-(Thiophen-2-ylmethyl)aniline (4p):[15d] Yellow liquid; 1H NMR
(400 MHz, CDCl3): δ = 7.24–7.17 (m, 3H), 7.04–7.00 (m, 1H), 6.97 (dd,
J = 5.0, 3.5 Hz, 1H), 6.75 (t, J = 7.3 Hz, 1H), 6.68 (d, J = 7.5 Hz, 2H),
4.52 (s, 2H), 4.05 (s, 1H). 13C{1H} NMR (151 MHz, CDCl3): δ = 147.72,
143.04, 129.41, 126.99, 125.18, 124.73, 118.22, 113.28, 43.63. HRMS
(ESI):[M + H]+, Calculated 190.0690, found 190.0700.
N-Phenethylaniline (4q):[15d] Yellow liquid; 1H NMR (600 MHz,
CDCl3): δ = 7.33 (t, J = 7.4 Hz, 2H), 7.27–7.22 (m, 3H), 7.19 (dd, J =
8.4, 7.5 Hz, 2H), 6.72 (t, J = 7.3 Hz, 1H), 6.63 (d, J = 7.7 Hz, 2H), 3.75
(s, 1H), 3.41 (t, J = 7.1 Hz, 2H), 2.93 (t, J = 7.0 Hz, 2H). 13C{1H} NMR
(151 MHz, CDCl3): δ = 148.06, 139.41, 129.42, 128.93, 128.74, 126.56,
117.65, 113.16, 45.19, 35.62. HRMS (ESI):[M + H]+, Calculated
198.1283, found 198.1304.
(400 MHz, CDCl3): δ = 6.80 (d, J = 8.9 Hz, 2H), 6.59 (d, J = 8.9 Hz,
2H), 3.75 (s, 3H), 2.81 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ =
152.21, 143.81, 115.03, 113.79, 56.00, 31.78. HRMS (ESI):[M + H]+,
Calculated 138.0919, found 138.0936.
4-Methyl-N-methylaniline (5e):[49] Yellow liquid; 1H NMR (400 MHz,
CDCl3): δ = 7.00 (d, J = 8.1 Hz, 2H), 6.55 (d, J = 8.4 Hz, 2H), 2.82 (s,
3H), 2.24 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ = 147.28, 129.82,
126.63, 112.75, 31.25, 20.52. HRMS (ESI):[M + H]+, Calculated
122.0970, found 122.0994.
N-Ethylaniline (5h):[50] Yellow liquid; 1H NMR (400 MHz, CDCl3): δ =
7.20 (t, J = 7.9 Hz, 2H), 6.72 (t, J = 7.3 Hz, 1H), 6.63 (d, J = 7.7 Hz,
2H), 3.17 (q, J = 7.2 Hz, 2H), 1.28 (d, J = 7.1 Hz, 3H). 13C{1H} NMR
(100 MHz, CDCl3): δ = 148.56, 129.33, 117.31, 112.85, 112.79, 38.57,
15.02. HRMS (ESI):[M + H]+, Calculated 122.0970, found 122.0992.
N-Isopropylaniline (5i): 1H NMR (400 MHz, CDCl3) δ = 7.16 (dd, J =
8.5, 7.4 Hz, 2H), 6.68 (d, J = 7.3 Hz, 1H), 6.59 (dd, J = 8.5, 0.9 Hz,
2H), 3.62 (dq, J = 12.5, 6.3 Hz, 1H), 3.44 (s, 1H), 1.21 (d, J = 6.3 Hz,
6H). 13C{1H} NMR (101 MHz, CDCl3) δ = 147.65, 129.41, 117.09,
113.37, 44.34, 23.17. HRMS (ESI):[M + H]+, Calculated 136.2180,
found 136.1145.
N-(Cyclohexylmethyl)aniline (4r):[15d] Yellow liquid; 1H NMR
(600 MHz, CDCl3): δ = 7.17 (t, J = 7.9 Hz, 2H), 6.68 (t, J = 7.3 Hz,
1H), 6.60 (d, J = 7.7 Hz, 2H), 3.71 (s, 1H), 2.95 (d, J = 6.7 Hz, 2H),
1.86–1.52 (m, 6H), 1.33–1.11 (m, 3H), 0.99 (qd, J = 12.4, 2.9 Hz, 2H).
13C{1H} NMR (150 MHz, CDCl3): δ = 148.76, 129.35, 116.99, 112.73,
50.72, 37.68, 31.44, 26.72, 26.11 HRMS (ESI):[M + H]+, Calculated
190.1596, found 190.1611.
N-Methylaniline (5):[15d] Yellow liquid; 1H NMR (400 MHz, CDCl3):
δ = 7.23–7.17 (m, 2H), 6.72 (t, J =7.3 Hz, 1H), 6.67–6.58 (m, 2H), 2.85
(s, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ = 149.46, 129.33, 117.38,
112.55, 30.86. HRMS (ESI):[M + H]+, Calculated 108.0813, found
108.0814.
N-Butylaniline (5j):[15d] 1H NMR (400 MHz, CDCl3) δ = 7.23–7.13
(m, 2H), 6.69 (t, J = 7.3 Hz, 1H), 6.61 (d, J = 7.7 Hz, 2H), 3.12 (t, J =
7.1 Hz, 2H), 1.65–1.57 (m, 2H), 1.44 (dq, J = 14.4, 7.3 Hz, 2H), 0.97
(t, J = 7.3 Hz, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ = 148.70, 129.35,
117.21, 112.83, 43.82, 31.83, 20.45, 14.05. HRMS (ESI):[M + H]+, Cal-
culated 150.1283, found 150.1299.
N-Hexylaniline (5k):[51] 1H NMR (600 MHz, CDCl3) δ = 7.17 (t, J =
7.9 Hz, 2H), 6.68 (t, J = 7.3 Hz, 1H), 6.60 (d, J = 7.7 Hz, 2H), 3.60 (s,
1H), 3.10 (t, J = 7.1 Hz, 2H), 1.65–1.59 (m, 2H), 1.43–1.37 (m, 2H),
1.36–1.29 (m, 4H), 0.92–0.88 (m, 3H). 13C{1H} NMR (151 MHz, CDCl3)
δ = 148.67, 129.35, 117.20, 112.81, 44.14, 31.80, 29.68, 27.01, 22.78,
14.20. HRMS (ESI):[M + H]+, Calculated 178.1596, found 178.1629.
4-Fluoro-N-methylaniline (5a):[46] Yellow liquid; 1H NMR (400 MHz,
CDCl3): δ = 6.90 (t, J = 8.8 Hz, 2H), 6.54 (dd, J = 9.0, 4.4 Hz, 2H),
2.81 (s, 3H). 13C{1H} NMR (151 MHz, CDCl3): δ = 155.93 (d, J1 C-F =
234.4 Hz), 145.81, 115.73 (d, J2 C-F = 22.3 Hz), 113.26 (d, J3 C-F =
7.3 Hz), 31.48. 19F{1H} NMR (377 MHz, CDCl3): –128.49. HRMS (ESI):[M
+ H]+, Calculated 126.0719, found 126.0743.
Methyl 4-Aminobenzoate (5ba):[47] White solid; 1H NMR (400 MHz,
CDCl3) δ = 7.84 (d, J = 8.7 Hz, 2H), 6.63 (d, J = 8.7 Hz, 2H), 4.08 (s,
2H), 3.85 (s, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ = 167.30, 150.97,
131.72, 119.83, 113.91, 51.72.
2-Phenyl-1H-benzo[d]imidazole (7):[29a] Yellowish solid; 1H NMR
(400 MHz, DMSO) δ = 12.89 (s, 1H), 8.18 (d, J = 7.1 Hz, 2H), 7.74–
7.42 (m, 5H), 7.20 (d, J = 3.8 Hz, 2H). 13C{1H} NMR (101 MHz, DMSO)
δ = 13C NMR (101 MHz, DMSO) δ = 151.21, 143.81, 135.00, 130.17,
129.83, 128.94, 126.43, 122.52, 121.66, 118.87, 111.31. HRMS (ESI):[M
+ H]+, Calculated 195.0922, found 195.0956.
2-(4-Fluorophenyl)-1H-benzo[d]imidazole (7m): Yellowish solid;
1H NMR (600 MHz, DMSO) δ = 12.93 (s, 1H), 8.22 (dd, J = 9.9, 3.2 Hz,
2H), 7.66 (d, J = 7.5 Hz, 1H), 7.53 (d, J = 7.5 Hz, 1H), 7.41 (t, J =
8.7 Hz, 2H), 7.20 (dt, J = 14.5, 6.7 Hz, 2H). 13C{1H} NMR (151 MHz,
DMSO) δ = 163.07 (d, J1 C-F = 247.3 Hz), 150.39, 143.76, 135.03,
128.73 (d, J3 C-F = 8.7 Hz), 126.81 (d, J4 C-F = 2.9 Hz), 122.58, 121.74,
Methyl 4-(N-Methylamino)benzoate (5bb):[16p] White solid; 1H
NMR (400 MHz, CDCl3) δ = 7.87 (d, J = 8.8 Hz, 2H), 6.55 (d, J =
8.8 Hz, 2H), 4.20 (s, 1H), 3.85 (s, 3H), 2.88 (s, 3H). 13C{1H} NMR 118.86, 116.05 (d, J2 C-F = 21.9 Hz), 111.35. 19F NMR (565 MHz,
(101 MHz, CDCl3) δ = 167.52, 153.02, 131.64, 118.36, 111.22, 51.64,
DMSO) δ = –111.13 (qd, J = 8.5, 5.5 Hz). HRMS (ESI):[M + H]+, Calcu-
lated 213.0828, found 213.0833.
30.27. HRMS (ESI):[M + H]+, Calculated 166.0868, found 166.0889.
1
Methyl 4-(N,N-Dimethylamino)benzoate (5bc):[48] White solid; H
2-(4-Methoxyphenyl)-1H-benzo[d]imidazole (7n):[52] White solid;
NMR (400 MHz, CDCl3): δ = 7.90 (d, J = 9.1 Hz, 2H), 6.65 (d, J =
1H NMR (400 MHz, DMSO) δ = 12.74 (s, 1H), 8.12 (d, J = 8.8 Hz, 2H),
9.0 Hz, 2H), 3.85 (s, 3H), 3.04 (s, 6H). 13C{1H} NMR (100 MHz, CDCl3): 7.56 (br, 2H), 7.23–7.07 (m, 4H), 3.84 (s, 3H). 13C{1H} NMR (101 MHz,
δ = 167.64, 153.35, 131.41, 117.15, 110.99, 51.65, 40.29. HRMS DMSO) δ = 160.63, 151.37, 128.03, 122.70, 122.07, 114.39, 55.35.
(ESI):[M + H]+, Calculated 180.1025, found 180.1041.
HRMS (ESI):[M + H]+, Calculated 225.1028, found 225.1045.
2,4,5-Trifluoro-N-methylaniline (5c): Yellow liquid; 1H NMR
(400 MHz, CDCl3): δ = 6.86 (ddd, J = 11.1, 10.0, 7.2 Hz, 1H), 6.45 (dt,
Computational Details: All the calculations were performed on
Gaussian-09 (revision D.01) program package.[53] PBEPBE DFT func-
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tional[54] and Popel's basis set with two polarization functions [6-
311G(d,p)] was used for all the atoms except Ru. We used double-
ꢁ quality LANL2DZ basis set with effective core potential for Ru
atom.[55] In order to differentiate the obtained stationary points as
minima structures or transition states, vibrational frequency calcula-
tions were performed at the same level of theory. DFT functional
and basis set was selected on the basis of previous reports on simi-
lar complexes.[34] Minimum energy reaction pathway (MERP) in
mass-weighted Cartesian coordinates was followed, wherever nec-
essary, with the help of intrinsic reaction coordinate (IRC) calcula-
tions to connect the obtained transition states and their reactants
and products.[56]
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Acknowledgments
A. K. gratefully thanks the Science and Engineering Research
Board, Department of Science and Technology (Grant DST–SERB
YSS/2015/000573), Board of Research in Nuclear Sciences, De-
partment of Atomic Energy (Grant BRNS–DAE 37(2)/20/13/2016)
and Council of Scientific and Industrial Research (Grant
01(2883)/17/EMR–II). H. K. S is thankful to Science and Engineer-
ing Research Board, Department of Science and Technology
(Grant DST–SERB SB/S2/RJN-004/2015). K. D., P. G. N and K. I.
thank IITG for research fellowship. We also thank the DST–FIST
program, Department of Chemistry at IITG, Param–Ishan and
CIF–IITG for various instrumental and computational facilities.
Keywords: Alkylation · Dehydrogenation · Homogeneous
catalysis · Pincer complexes · Ruthenium
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Received: September 3, 2019
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© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
Catalytic N-Alkylation
A solvent-free, efficient atom-economi-
cal N-alkylation and dehydrogenative
coupling of amines catalyzed by a
ruthenium–pincer is reported. Sodium
alkoxide generated in situ from alco-
hols using sodium serve a dual role as
alkyl precursor and as a base. The wa-
ter formed in the reaction promotes
the catalytic cycle by regenerating al-
cohol from sodium alkoxide.
K. Das, P. G. Nandi, K. Islam,
H. K. Srivastava,* A. Kumar* ........ 1–13
N–Alkylation of Amines Catalyzed
by a Ruthenium–Pincer Complex in
the Presence of in situ Generated
Sodium Alkoxide
DOI: 10.1002/ejoc.201901310
Eur. J. Org. Chem. 0000, 0–0
www.eurjoc.org
13
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim