Selective N-alkylation of amines with alcohols by using non-metal-based acid-base cooperative catalysis

Article abstract of DOI:10.1002/chem.201102446

Learning to cooperate: A straightforward method for the selective N-mono- and dialkylation of amines with alcohols by means of non-metal-based catalysis promoted by TAPC is reported (see scheme). Selectivity of the N-mono- and dialkylation, substrate scope and functional-group tolerance are highlighted with respect to each amine (1° and 2°; aromatic and aliphatic) and alcohol (1°, 2° and 3°; benzylic and aliphatic) component. Copyright

Full text of DOI:10.1002/chem.201102446

DOI: 10.1002/chem.201102446
Selective N-Alkylation of Amines with Alcohols by Using Non-Metal-Based
Acid–Base Cooperative Catalysis
Ya Du,[a, c] Shunsuke Oishi,[a] and Susumu Saito*[a, b]
Higher amines are widely used in both the bulk and fine
chemical industry for the synthesis of fundamental materials,
such as additives, dyes and agrochemicals.[1] Therefore, the
development of a selective N-alkylation method that is cost
effective, salt free and environmentally benign is of consid-
erable interest. Indeed, reactions involving the N-alkylation
of amines with alcohols[2] (R OH) in place of R X, where
À
À
X denotes halide, tosylate, mesylate, or triflate,[1d,e] are well
À
documented. To promote the N-alkylation using R OH,
metal-based catalyses have been developed. These reactions
mainly use benzylic-type and saturated alcohols with catalyt-
ic Ru,[3] Ir,[4] Cu,[5a–e] Ni,[5f] and Ag[5g,h] species. In addition,
Lewis acidic metals[6] and Pd[7] catalysts are also competent
mediators of N-alkylation with benzylic-type secondary alco-
hols and allylic alcohols. Herein, we report a novel and
Scheme 1. General scheme for TAPC-catalysed selective N-alkylation of
amines 1 using alcohols 2.
À
straightforward method for the N-alkylation with R OH
(18, 28 and 38) using non-metal-based[8a] catalysis promoted
by 1,3,5-triazo-2,4,6-triphosphorine-2,2,4,4,6,6-hexachloride[9]
(TAPC). This new reaction involves substitution (SN) at the
alcohols sp3 carbon atom bearing the hydroxyl group
(Scheme 1),[8b] by which selective N-mono- and dialkylation
were successfully achieved.
Scheme 2. Selective N-mono- and dibenzylation of 1a.
Table 1. N-Alkylation of 1a with 2a under different conditions.[a]
Entry
Catalyst
1a:2a[b]
Yield[%][c]
precursor ([mol%])
1
2
3
4
5
6
7
8
9
TAPC (5)
TAPC (4)
TAPC (5)
2:1
1:2.5
2:1
2:1
2:1
2:1
2:1
2:1
2:1
2:1
92 (75)[d]
<1 (80)[e]
45[f]
<1
23
Treatment of aniline (1a, 2 equiv) with benzyl alcohol
(2a, 1 equiv) in the presence of TAPC (5 mol% with respect
to 2a) at 1608C for 12 h in 1,2,4-trimethylbenzene (1,2,4-
TMB) under Ar using a sealed reactor,[10] followed by
column chromatography on silica gel, gave mono-alkylated
amine 3aa in 92% yield (Scheme 2, Table 1, entry 1).[11] The
tertiary amine resulting from N-dialkylation was obtained in
about 7% yield, as determined by GC-MS and 1H NMR
spectroscopy. Formation of benzyl chloride and dibenzyl
ether was found to be negligible[12] by GC-MS analysis. In
the absence of solvent, the yield of 3aa decreased to 75%
H3PO4 (30)
HCl[i] (30)
HCl[i] (30) + H3PO4 (15)
5a (5)
51
22[g]
5b (30)
5a (5) + 5b (30)
5a (5) + NMe4Cl (30)
46[g]
81[h]
10
26
[a] Unless otherwise specified, the reaction was carried out with 1a
(4 mmol), 2a (2 mmol) and catalyst precursor (0.1 mmol: 0.09m) in 1,2,4-
TMB (0.5 mL) at 1608C for 12 h. [b] Molar ratio of components 1a and
2a in the reaction mixture at t=0. [c] Yield of crude product 3aa deter-
1
mined by H NMR spectroscopy using 1,1,2,2-tetrachloroethane as an in-
ternal standard. [d] Without solvent. [e] Isolated yield of 4aa;
1a:2a:TAPC=40:100:4 ([TAPC]0 =0.12m). [f] 1408C, 12 h. [g] 1a
(3.4 mmol) was used. [h] 1a (2.8 mmol) was used. [i] 2m Solution in Et2O.
[a] Dr. Y. Du, S. Oishi, Dr. S. Saito
Department of Chemistry, Graduate School of Science
Nagoya University, Chikusa, Nagoya 464-8602 (Japan)
Fax : (+81)52-789-5945
E-mail: saito.susumu@f.mbox.nagoya-u.ac.jp
(entry 1). Addition of water (0.3 and 2.0 equiv with respect
to 2a) to the solute at 258C prior to reaction initiation did
not prevent the reaction from proceeding at 1608C (3aa was
recovered in 98 and 90%, respectively). Finally, a change in
the ratio of 1a/2a from 2:1 to 1:2.5 resulted exclusively in
N-dialkylation, giving 4aa in 80% yield (entry 2).[13]
[b] Dr. S. Saito
Institute for Advanced Research, Nagoya University
Chikusa, Nagoya 464-8601 (Japan)
[c] Dr. Y. Du
Current Address: Department of Chemistry
Colorado State University (USA)
Control reactions were performed to probe the involve-
ment of Brønsted acid catalysts that might be generated in
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201102446.
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Chem. Eur. J. 2011, 17, 12262 – 12267

COMMUNICATION
situ, such as H3PO4, HCl, or a combination of these two. In
fact, these catalysts were found to decelerate the reaction
rate (entries 4–6). Convinced that simple Brønsted acid cat-
alysis was not operative, we pursued time profiles of the re-
action course using 31P{1H} NMR spectroscopy in order to
identify the resting state of the P-based catalyst. According
to the time-dependent spectra, the singlet signal of TAPC (d
= 20.7 ppm in 1,2,4-TMB/CDCl3 at 258C) immediately di-
minished when mixed with 1a and 2a at 258C and disap-
concomitant liberation of 5b during N-alkylation. Since
Me4NCl did not enhance the reactivity of 5a (entry 10) and
H3PO4 was totally inert (entry 4), 5a and 5b (thus H+
+
ClÀ) acted synergistically to catalyze the reaction.[12,15]
To elucidate the mechanism with which 5b (HCl) and the
resting state P species 5a catalyzed the reaction of 1a with
2a, additional control experiments were carried out (1608C,
12 h). When [D30]5a (consisting of 6ACHTNUGRTNEUNG(C6D5NH), 5 mol%) +
5b (30 mol%) were used with 1a:2a=1.4:1, 3aa was ob-
tained in 81% yield without any incorporation of deuterium.
Similarly, 3aa was obtained from 1a:2a=1.4:1 in 98% yield
when 5c[16] ( mol%) was used in combination with 5b (30
mol%). In this case N-alkylation of 1,2-diaminobenzene was
not detected by GC-MS. These experiments strongly suggest
that 5a is stable on the reaction timescale. Phosphazene 5a
is much more basic than 1a, since upon protonation of 5a
with 5b delocalization of the counterion of ClÀ is reinforced
in the six-membered phosphazene ring system. The en-
hanced catalytic activity of 5a + 5b (=5a + 1a + HCl)
being less acidic than 5b suggests that 5a + 5b serves as a
superior acid–base cooperative catalyst in our reaction.
Mechanistically, 1a in the 5a + 5b complex could undergo
N-alkylation with 2a (thus bimolecular reaction) giving 3aa
in a concerted fashion (e.g., TS) after recombinant of hydro-
gen bonds[17] in 5a + 5b may or may not occur at the secon-
dary coordination sphere[18] of 5a.[19,20] Another important
role of HCl is to regenerate the resting state 5a more effec-
tively. When 5d[21] (5 mol% with respect to net 2a) alone
was used with 1a:2a=2.9:1, 3aa was obtained in 43% yield.
In contrast, the yield of 3aa was increased to 98% using 5d
(5 mol%) + 5b (30 mol%) with 1a:2a=2.4:1. In this last
reaction, 5a (+5b) was again the only species observable by
31P{1H} NMR analysis.
peared completely at elevated temperatures (1608C,
t
<20 min). Instead, only one singlet (d = (1.2Æ0.1) ppm in
1,2,4-TMB/CDCl3) was detected, which retained the same d
position at all time periods of sampling (up to t = 12 h).
To elucidate the resting state structure of the P species,
we attempted its isolation from a solution of 1a and TAPC.
Two chemical entities, 5a[14] and 5b, were separated from
the mixture through a simple filtration–wash technique, and
both were obtained in quantitative yields (calculated based
on a molar amount of P and Cl, respectively). When 5a was
added to a reaction mixture containing 1a, 2a and the struc-
turally modified TAPC (its structure was not clarified up to
that time), the 31P{1H} NMR signal of 5a entirely over-
lapped at d = 1.23 ppm with the signal consistently observed
throughout the N-alkylation. This strongly suggests that 5a
is the resting state of the catalyst.
Given the understanding gained in our NMR experiments,
we examined 5a, 5b, or a combined mixture of these two
compounds as potential catalysts in the reaction (Table 1,
entries 7–9). Of these, 5a + 5b showed the highest catalytic
performance. To get an insight into the kinetic profiles of
catalysis promoted by each of these four species, 5a, 5b, 5a
+ 5b and TAPC, yields of 3aa were plotted as a function of
reaction time (Figure 1). The 5a + 5b curve has a slope sim-
ilar to that of the TAPC curve, but with a lower initial reac-
tion rate. When a suspension containing 5a + 5b was
heated to 1608C, complete dissolution of the solids took
about 30 min, suggesting that the induction period (t <1 h)
is partially related to the time required to make the reaction
mixture homogeneous. In summary, these experiments clear-
ly demonstrate that TAPC readily generates 5a in situ with
Encouraged by these findings, which demonstrate TAPC
to be a competent catalyst precursor with easy handling, we
next examined the substrate scope of our N-alkylation. The
scope was investigated under optimal reaction conditions for
both N-mono- (1:2:TAPC=2:1:0.05) and dialkylation
(1:2:TAPC=0.4:1:0.04) in 1,2,4-TMB. The results are sum-
marized in Table 2.
Coupling reactions between anilines 1a–l and electroni-
cally diverse benzylic primary alcohols 2a–m gave the ex-
pected N-mono- or dialkylation products 3ab–ia or 4ab–ia
selectively in good to high yields (entries 1–20). Further-
more, our results demonstrated that it is feasible to discrimi-
nate one NH2 group from another under the established
conditions. Although sulfonamides are readily alkylated
Figure 1. NMR yield(%) of 3aa obtained from the reaction of 1a with
&
^
2a (2:1) at 1608C vs. reaction time (t, h). ( ): with TAPC (5 mol%); ( ):
with
alcohols
according
to
several
established
~
*
with 5a (5 mol%) + 5b (30 mol%); ( ): with 5b (30 mol%); ( ): with
5a (5 mol%). Net [1a]0 was kept identical for each run.
methods,[2c,3h,i,5b] the sulfonamide moiety of aniline 1k re-
Chem. Eur. J. 2011, 17, 12262 – 12267
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www.chemeurj.org
12263

S. Saito et al.
Table 2. Selective N-alkylation of various amines 1 with alcohols 2.[a]
Less reactive alcohols, such
as fully saturated alcohols, were
also tested (Table 3). By merely
elevating the reaction tempera-
ture, secondary amines 3an–at
and tertiary amines 4au–aw, de-
rived by N-mono- and dialkyla-
tion, respectively, were ob-
tained in good to excellent
yields (entries 1–10). The carbo-
Entry
Amine 1
Alcohol 2
3 (Yield[%])[b,c]
4 (Yield[%])[b,d]
conditions A[a]
conditions B[a]
1
2
3
4
5
6
7
8
9
1a (X=H)
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1b (X=4-OMe)
1c (X=4-Me)
1d (X=3-Me)
1e (X=2-Me)
1 f (X=4-F)
1g (X=4-Cl)
1h (X=3-CF3)
1i (X=3-NO2)
1j
2b (Y=4-OMe)
2c (Y=3-MeO)
2d (Y=4-Me)
2e (Y=3-Me)
2 f (Y=2-Me)
2g (Y=4-F)
2h (Y=4-Cl)
2i (Y=4-Br)
2j (Y=4-I)
2k (Y=2-I)
2l (Y=4-CF3)
2m (Y=4-NO2)
2a (Y=H)
2a
2a
2a
2a
2a
2a
2a
2a
2a
3ab (55)
3ac (83)
3ad (82)
3ae (86)
3af (60)
3ag (98)
3ah (81)
3ai (81)
3aj (94)
3ak (63)
3al (83)
3am (81)[f]
3ba (76)
3ca (77)
3da (98)
3ea (96)
3 fa (81)[g]
3ga (79)
3ha (61)
3ia (78)
3ja (99)
3ka (81)
3la (29)
4ab (51)
4ac (95)
4ad (86)
4ae (71)
4af (56)
4ag (90)
4ah (82)
4ai (81)
4aj (57)
4ak (57)
4al (69)
4am (34)[h]
4ba (96)
4ca (62)
4da (90)
4ea (61)
4 fa (76)
4ga (89)
4ha (72)[i]
4ia (71)
3ja (99)[j]
4ka (47)
4la (34)
cation-developing
pathway
(SN1) is unlikely to occur with
saturated primary alcohols in-
cluding MeOH. Even at a high
temperature, secondary alcohol
2q and the interior (Z)-olefin
of 2r did not undergo b-elimi-
nation or isomerization, respec-
tively (entries 4 and 5). The a/g
(>99%) and/or E/Z (>99%)
selectivities of the reaction with
allylic alcohol 2s were excellent
(entry 6). Tertiary alcohol 2t
was also compatible with the
10[e]
11
12
13
16
14
15
17
18
19
20
21
22
23
present
reaction
(entry 7),
1k
1l
which excludes any possibility
of a borrowing hydrogen mech-
anism.[2–5] A second intramolec-
2a
[a] Unless otherwise specified, 1:2:TAPC=2:1:0.05, [TAPC]0 = ~0.09m (conditions A) or 1:2:TAPC=
0.4:1:0.04, [TAPC]0 = ~0.11m (conditions B) was used in 1,2,4-TMB at 1608C for 15 h. [b] Isolated yield.
[c] Based on 2. [d] Based on 1. [e] 36 h. [f] 1:2:TAPC=2:1:0.1; [TAPC]0 = ~0.04m, 11 h. [g] 1808C, 24 h. ular alkylation took place
[h] Detected by GC-MS. [i] 1:2:TAPC=0.4:1:0.08; [TAPC]0 = ~0.23m. [j] No dialkylation.
smoothly upon reaction of diols
2u and 2v, giving pyrrolidine
mained untouched in the presence of the NH2 of the aniline,
which was selectively N-mono- or dialkylated to afford 3ka
and 4ka, respectively (entry 22).
and piperidine derivatives 4au and 4av, respectively, in good
yields (entries 8 and 9). N-Dimethylation with MeOH pro-
ceeded as well using a smaller amount of TAPC to give 4aw
almost quantitatively (entry 10).
Table 3. Selective N-alkylation of 1a with various alcohols 2.[a]
Entry
Alcohol 2
Conditions
T [8C] t [h]
Product
amine
Yield[%][b]
1
2
3
4
5
2n
2o
2p
2q
2r
2s
2t
2u
180
180
180
200
160
160
180
200
200
200
24
24
24
36
72
36
72
36
36
36
3an
3ao
3ap
3aq
3ar
3as
3at
4au
4av
4aw
84
94 (74)[e]
82
75
70
94
78
85
82
97
6
7
8[c]
9[c]
10[d]
2v
MeOH (2w)
[a] Unless otherwise specified, 1a:2:TAPC=2:1:0.05 was used in 1,2,4-
TMB ([TAPC]0 = ~0.09m). [b] Yield of isolated, purified product, based
on 2. [c] 1a:2:TAPC=2:1:0.1; [TAPC]0 = ~0.18m. [d] 1a:2w:TAPC=
1:30:0.025; [TAPC]0 = ~0.017m. [e] Isolated yield of 4ao:1a:2o:TAPC=
0.4:1:0.04; [TAPC]0 = ~0.10m.
The N-benzylation of more basic, aliphatic amines was
also examined (Table 4). In the reaction of 1p (entry 4), no
reaction was observed when using Brønsted acid HCl + 1p
(30 mol% each) alone.[12] Although elevated temperatures
12264
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Chem. Eur. J. 2011, 17, 12262 – 12267

Selective N-Alkylation of Amines
COMMUNICATION
Having established the utility of TAPC-based catalysis for
the nucleophilic substitution at the COH carbon with
amines, we investigated the possibility of a stereospecific
SN2 reaction using optically pure (S)-2x (Scheme 4). Rather
Scheme 4. Partial Walden inversion of chiral alcohol 2x. a) TAPC
(5 mol%): 92% (9% ee); b) 5b (5 mol%): 77% (6% ee); c) 5a
(5 mol%): 30% (51% ee). [a] Net ratio, in which 1a incorporated into 5
is included.
acidic reagents, TAPC and 5b, furnished N-alkylation prod-
uct 3ax in less than 10% ee. In contrast, 51% ee in favor of
(R)-3ax was obtained in the presence of catalytic 5a
(5 mol%) under milder catalysis. The original absolute con-
figuration maintained in recovered (S)-2x (>98% ee). Fur-
ther tuning of the reaction conditions could potentially pro-
mote a more satisfactory Walden inversion of chiral alco-
hols, for which water is the main byproduct. Improvement
Table 4. N-Mono- and dibenzylation of various aliphatic amines 1 with
2a.[a]
Entry
Amine 1
Conditions
T [8C]
Product
amine
Yield[%][b]
t [h]
1
2
3
1m
1n
1o
1p
1q
1r
1s
1t
1u
200
200
200
200
200
180
180
200
200
200
200
200
36
36
36
15
36
48
36
36
36
24
36
36
3ma
3na
3oa
3pa
3qa
4ra
4sa
4ta
4ua
4va
4wa
4xa
74 (80)[f]
98 (65)[f]
90
4[c]
5[c]
6[d,e]
7[d]
8
80
91
73
81
91
94
16
89
of catalysts for this salt-free (phosphorusACTHNUTRGNE(NUG III)- and azodicar-
boxylate-free) N-alkylation alternative to the Mitsunobu re-
action[22] is now underway. Furthermore, structural diversity
[9a–c]
of poly(phosphazene)s (Cl2P=N)n
and metal complexes
of phosphazenes[9d] are available, so that the present basic
research has potential to expand to recyclable solid and
metal-based catalysts.
9
10
11[d]
12[d]
NH
1w
1x
(1v)/H2O
60
[a] Unless otherwise specified, 1:2a:TAPC=2:1:0.05 was used in 1,2,4-
TMB; [TAPC]0 = ~0.09m. [b] Isolated yield based on 2a.
[c] 1:2a:TAPC=2:1:0.1; [TAPC]0 = ~0.18m. [d] 1:2a:TAPC=1:1:0.05;
[TAPC]0 = ~0.1m. [e] DMF (5 mol%) was added. [f] Yield of isolated, di-
alkylation product 4ma (entry 1) or 4na (entry 2): 1:2a:TAPC=
0.4:1:0.04; [TAPC]0 = ~0.09m.
Experimental Section
TAPC (34.8 mg, 0.1 mmol), aniline (1a) (373 mg, 4 mmol), benzyl alcohol
(2a) (216 mg, 2 mmol) and 1,2,4-trimethylbenzene (0.5 mL) were added
sequentially to a dry and sealed flask, stoppered by a Youngꢁs stopcock,
under argon atmosphere (Caution! rigorous exclusion of air from the re-
action mixture is strongly recommended for all the N-alkylation reactions
using TAPC.). The reaction mixture was stirred at 1608C for 15 h and
was cooled to room temperature and purified using a middle-pressure
preparative LC to give N-benzylaniline (3aa) as a colorless oil (337 mg,
1.84 mmol, 92%).
were generally required, primary and secondary amines
were well suited for the reaction, giving secondary and terti-
ary amines in high yields, respectively (entries 1–9, 11, and
12). Aqueous ammonia underwent N-tribenzylation[3k,4i] to
give 4va, albeit in low yield (entry 10). Because of the inher-
ent nature of weak-acid/weak-base cooperative catalysis
under fairly neutral pH conditions, elevated temperatures
were required to obtain a good product yield. Nonetheless,
prolonged heating at 160–2008C is acceptable at least for an
industrial process, because the recovered extra heat energy
can be reused for other purposes.
Acknowledgements
This work was partially supported by a Grant-in-Aid for Basic Research
(B) from JSPS and for Scientific Research on Priority Areas “Advanced
Molecular Transformations of Carbon Resource” from MEXT, and by
funds from Asahi Glass, Asahi Kasei Chemicals, Daiso, Kuraray, Mitsu-
bishi Chemical, Mitsui Chemicals, Nissan Chemical Ind., and Sumitomo
Chemical Co.. Authors wish to thank GCOE in Chemistry, Nagoya Univ.
(NU) and Prof. R. Noyori (NU & RIKEN) for fruitful discussions.
A substrate combination with the least reactive 1o and
2o was also tested (Scheme 3). The N-alkylation proceeded
to give the product 3oo in <50% yield.
Keywords: alcohols · alkylation · cooperative catalysis ·
hydrogen bonds · nucleophilic substitution
Scheme 3. Aliphatic amine–alcohol combination.
Chem. Eur. J. 2011, 17, 12262 – 12267
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
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S. Saito et al.
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[10] All reactions were carried out in flasks sealed by a Youngꢁs stopcock
under Ar, so that HCl and water were retained in the reaction
vessel.
[11] A large-scale reaction using 60 mmol of 2a proceeded to give 3aa in
90% yield.
[12] Involvement of a benzyl or alkyl chloride as a reaction intermediate
cannot be fully ruled out. Given that these species are not observed
in appreciable quantities and that HCl alone barely catalyzes many
of our reactions, participation of a phosphazene such as 5a seems
likely. See also ref. [15].
[13] A good correlation between ratios 1a:2a and product yields of 3aa
and 4aa was observed, which was visualized by ESI, Figure S1 in the
Supporting Information. Selectivity of N-monoalkylation was further
improved by using a smaller amount of 1a with a dummy substrate:
when we conducted the reaction at 1608C for 24 h using a ratio of
1a/2a/PhNMe2 =0.7:1:0.7 in the presence of 5a (5 mol%) + 5b
(30 mol%), 3aa and 4aa were obtained in 85% and 7% yield
(based on 1a + 5b), respectively, with full conversion of 2a.
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+ 5b) and 5b appears to be only modest in the reaction of 1a and
2a, a significant difference in catalytic activity was observed in the
reaction of 1a and 2n (Table 3, entry 1): when 5b (30 mol%) was
used, only 10% of 3an was obtained. The use of more neutral 5a
(5 mol%) alone provided 3an in better yield (30%).
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breaking and making in [N···C···O]ꢀ should be kept near to 1808.
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[19] A cationic phosphazene and its counterion can work cooperatively;
for examples, see: a) D. Uraguchi, U. Ueki, T. Ooi, J. Am. Chem.
12266
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Chem. Eur. J. 2011, 17, 12262 – 12267

Selective N-Alkylation of Amines
COMMUNICATION
Soc. 2008, 130, 14088–14089; b) D. Uraguchi, U. Ueki, T. Ooi, Sci-
ence 2009, 326, 120–123.
[20] A chloride ion is potentially capable of functioning as a base in a
hydrocarbon solvent: R. Mahrwald, B. Gꢄndogan, J. Am. Chem.
Soc. 1998, 120, 413–414.
[21] Synthesized according to the literature procedure: D. Kumar, N.
Singh, K. Keshav, A. J. Elias, Inorg. Chem. 2011, 50, 250–260.
[22] O. Mitsunobu, Synthesis 1981, 1–28.
Received: August 6, 2011
Published online: September 21, 2011
Chem. Eur. J. 2011, 17, 12262 – 12267
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
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