Selective N,N-dibenzylation of primary aliphatic amines with dibenzyl carbonate in the presence of phosphonium salts

Article abstract of DOI:10.1021/jo049840c

In the presence of catalytic amounts of tetraalkylphosphonium salts and under solventless conditions, primary aliphatic amines (RNH₂: R = PhCH₂, Ph(CH₂)₂, n-decyl, and 1-naphthylmethyl) are efficiently N-benzylated to the corresponding RN(CH₂Ph) ₂, using dibenzyl carbonate as the benzylating reagent. Compared to the reaction run without salt, where the competitive formation of the benzyl carbamate is favored, the phosphonium salt promotes high selectivity toward the benzylated amine and an increase of the reaction rate as well. However, in a single case explored for an amino acidic compound, namely 4-(aminomethyl) benzoic acid [4-(NH₂CH₂)C₆H₄CO ₂H], both N,N-dibenzylation and esterification of the acid group were observed. Analysis of the IR vibrational modes of benzylamine in the presence of tetrabutylphosphonium bromide supports the hypothesis that this enhanced selectivity may be due to an acid-base interaction between the salt and the amine, which increases the steric bulk of the amine and favors attack of the nucleophile on the less hindered alkyl terminus of dibenzyl carbonate.

Full text of DOI:10.1021/jo049840c

Selective N,N-Diben zyla tion of P r im a r y
Alip h a tic Am in es w ith Diben zyl Ca r bon a te
in th e P r esen ce of P h osp h on iu m Sa lts
Bn)X, respectively, eqs 1 and 2, Scheme 2]; however,
because of the reversibility of the BAc2 pathway, the
benzylated compound can be obtained as the sole product
(
eq 3).3
Alessandro Loris, Alvise Perosa, Maurizio Selva,* and
Pietro Tundo
Dipartimento di Scienze Ambientali dell’Universit a` Ca’
Foscari, Calle Larga S. Marta 2137, 30123 Venezia, Italy
The use of stronger nitrogen bases results in a similar
competitive alkylation/acylation sequence through a nu-
6
cleophilic catalysis. This reaction, however, yields ulti-
mately only benzylated derivatives: at 135 °C, indoles
and carboxylic acids react with DBnC in the presence of
DABCO (or DBU) as a base to give N-benzylindoles and
selva@unive.it
Received J anuary 27, 2004
7
Abstr a ct: In the presence of catalytic amounts of tetraal-
kylphosphonium salts and under solventless conditions,
primary aliphatic amines (RNH2: R ) PhCH2, Ph(CH2)2,
n-decyl, and 1-naphthylmethyl) are efficiently N-benzylated
to the corresponding RN(CH2Ph)2, using dibenzyl carbonate
as the benzylating reagent. Compared to the reaction run
without salt, where the competitive formation of the benzyl
carbamate is favored, the phosphonium salt promotes high
selectivity toward the benzylated amine and an increase of
the reaction rate as well. However, in a single case explored
for an amino acidic compound, namely 4-(aminomethyl)ben-
zoic acid [4-(NH2CH2)C6H4CO2H], both N,N-dibenzylation
and esterification of the acid group were observed. Analysis
of the IR vibrational modes of benzylamine in the presence
of tetrabutylphosphonium bromide supports the hypothesis
that this enhanced selectivity may be due to an acid-base
interaction between the salt and the amine, which increases
the steric bulk of the amine and favors attack of the
nucleophile on the less hindered alkyl terminus of dibenzyl
carbonate.
benzyl esters, respectively. It is notable that the same
reactions can be dramatically accelerated through the
combined use of microwave irradiation and of ionic
liquids.8
A different situation occurs with zeolite catalysts such
as MY faujasites (M ) Na, K): at 130-150 °C, DBnC
reacts with primary aromatic amines through a direct
B
Al2 pathway, and because of the amphoteric/steric
properties of the zeolite, only mono-N-benzylanilines
9
(
XC
In all cases, DBnC-mediated benzylation reactions
produce only PhCH OH as a coproduct, which is recy-
6
H
4
NHBn, X ) H, p-NO
2
, p-Cl) are observed.
2
clable to the synthesis of DBnC itself.
With the aim of exploring new applications of dibenzyl
carbonate as a green alkylating agent, we decided to
investigate its reactivity with other N-nucleophiles,
particularly with primary aliphatic amines (2), and in
the presence of tetraalkylphosphonium or 1,3-dialkylim-
idazolium salts (3). These low-melting saltsssometimes
referred to as ionic liquids (IL)srepresent an alternative
class of recyclable environmentally benign reaction media
and catalysts:10 in fact, they possess weak-to-moderate
Lewis-acidic properties, high ionic conductivity, negligible
The benzylation reaction is widely used in organic
1
synthesis, most often as a protection protocol. The
reaction is frequently carried out with benzyl halides,
which although efficient for a number of N-, O-, and
2
11
S-nucleophiles, pose concerns because of their toxicity/
vapor pressure, and moderate-to-high thermal stability.
carcinogenicity and/or lachrymatory properties. To de-
velop green methodologies with a reduced impact on
Th e Rea ction of Ben zyla m in e w ith DBn C. Ben-
zylamine (2a ) was initially chosen as a model compound.
It was made to react with DBnC (the molar ratio 1/2a
was of 2.1) at 145-170 °C, in the presence of the following
salts: hexadecyltributylphosphonium bromide (3a ); tet-
rabutylphosphonium bromide (3b), ethyltriphenyl phos-
phonium iodide (3c), cetylpyridiunium chloride (3d ), and
1-butyl-3-methylimidazolium tetrafluoroborate (3e). Com-
pounds 3a -e were added in the range of 0.05-0.5 molar
equiv with respect to 2a . The reaction of 2a with DBnC
was also run without added salts. Results are reported
in Table 1.
health and environment, dibenzyl carbonate (PhCH
2
-
OCO CH Ph, DBnC, 1) offers a valid alternative as a
2
2
benzylating reagent. DBnC, in fact, prepared by trans-
esterification of the nontoxic dimethyl carbonate (DMC),3
is a low-melting and easy-to-handle solid whose reactivity
can be summarized as indicated (Scheme 1).4
Around room temperature, DBnC reacts exclusively
through a BAc2 mechanism and only the carboxybenzyl-
5
ation reaction takes place. At higher temperatures
(T g 130 °C), BAc2 and BAl2 mechanisms are competitive,
and the outcome depends on the nature of the nucleophile
Without added salt (entry 1), the conversion of the
substrate reaches 76 and 93%, after 5 and 3 h at 145 °C
and at 170 °C, respectively. In both cases, along with the
formation of dibenzyl- and tribenzylamine (compounds
and of the catalyst. For example, in the presence of K
at 180-200 °C, methylene-active compounds (ArCH
X ) CN, CO
C-carboxybenzyl derivatives [ArCH(Bn)X and ArCH(CO
2
CO
3
2
X,
2
Bn) react with 1 to give both C-benzyl and
2
-
(
6) Shieh, W.-C.; Dell, S.; Bach, A.; Repi cˇ , O.; Blacklock, T. J . J .
*
To whom correspondence should be addressed. Fax: +39 041 234
620.
1) March, J . Advanced Organic Chemistry, 4th ed.; Wiley: New
York, 1991.
Org. Chem. 2003, 68, 1954.
(7) Shieh, W.-C.; Lozanov, M.; Loo, M.; Repi cˇ , O.; Blacklock, T. J .
Tetrahedron Lett. 2003, 44, 4563.
(8) Shieh, W.-C.; Lozanov, M.; Repi cˇ , O. Tetrahedron Lett. 2003, 44,
6943.
8
(
(2) Greene, T. W.; Wuts, P. G. M. Protective Groups in Organic
Synthesis; Wiley-Interscience: New York, 1991.
(9) Selva, M.; Tundo, P.; Perosa, A. J . Org. Chem. 2001, 66, 677.
(10) Ionic Liquids as Green Solvents: Progress and Prospects; Rogers,
R. D., Seddon, K. R., Eds.; ACS Symp. Ser. Vol. 856; American
Chemical Society: Washington, DC, 2003.
(11) Ionic Liquid in Synthesis; Wasserscheid, P., Welton, T., Eds.;
Wiley-VCH: Weinheim, 2003.
(
3) Selva, M.; Marques, C. A.; Tundo, P. J . Chem. Soc., Perkin Trans.
1
1995, 1889.
(
(
4) Tundo, P.; Selva, M. Acc. Chem. Res. 2002, 35(9), 706-716.
5) Monache, G. D.; Di Giovanni, M. C.; Maggio, F.; Misiti, D.;
Zappia, G. Synthesis 1995, 1155.
1
0.1021/jo049840c CCC: $27.50 © 2004 American Chemical Society
Published on Web 05/06/2004
J . Org. Chem. 2004, 69, 3953-3956
3953

SCHEME 1. Syn th esis a n d Rea ctivity of DBn Ca
a
NuH: generic nucleophile.
SCHEME 2. Mon o-C-ben zyla tion of Active
Meth ylen es w ith DBn C a n d K CO
2 3
conversion of benzylamine decreases from 4 to 1 h
(compare entries 2-5). A similar behavior is observed in
the experiments run with tetrabutylphosphonium bro-
mide (3b) (entries 6-7). It should be noted, however, that
the larger amount of salts 3a ,b produces only modest
variation of the alkylation-to-carbamation selectivity,
from 86 to a maximum of 92% (entries 2a and 4).
Also, ethyltriphenylphosphonium iodide (3c) is effec-
tive for the reaction of benzylamine and DBnC: at 170
°C, tribenzylamine is obtained in 80% GC-yield with only
7
% of the carbamate 6a (entry 8).
In all cases, the use of compounds 3a -c allows isolated
TABLE 1. Rea ction of Ben zyla m in e (2a ) w ith DBn C (1)
in th e P r esen ce of Sa lts (3)
yields of the wanted product 5a in the range of 79-82%.
Ammonium as well as imidazolium salts do not show
the satisfactory performance of the phosphonium com-
pounds. When cetylpiridinium chloride and 1-butyl-3-
methylimidazolium tetrafluoroborate are employed, both
the reaction rate (in relation to the amount of the used
salt) and, mostly, the selectivity ratio SA/C (not over 77%,
entry 10) drop with respect to 3a -c (compare entries 2-8
and 9-11). Under the same conditions of entry 10, the
use of Aliquat 336 (methyltricaprylammonium chloride)s
not reported in Table 1sbecomes impracticable because
the salt decomposes during the reaction and a complex
mixture of products forms.
products
molar
ratio
a
(%, GC)
Yb
added
salt
T
t
conv
entry
1
(2a :1:3) (°C) (h) (%) 4a 5a 6a (5a , %)
none
1:2
145
70
5
3
2
4
2
1
1
1
2
76 21
5 45
1
93 22 29 33
100 19 58 13
100 13 64 14
2
2
3
4
a
b
3a :
C16H33-
PBu3Br
1:2:0.05 170
1:2:0.1 170
1:2:0.21 170
100
3
81
9
7
6
9
80c
81c
100 11 75
.75 100
100
1
85
86
5
6
7
1:2:0.3 170
1:2:0.3 170
1:2:0.5 170 0.75 100
3b:
Bu4PBr
100 <1 80 10
82c
1
82
7
d
(
78 )
c
8
3c:
1:2:0.26 170 1.75 100
5
80
7
79
Reaction of P r im ar y Aliph atic Am in es with DBn C.
A second set of experiments was undertaken to examine
the reactivity of different primary aliphatic amines. At
170 °C, phenethyl-, n-decyl-, and 1-naphthylmethyla-
mines (2b-d , respectively) and 4-(aminomethyl)benzoic
acid (2e) were made to react with DBnC in the presence
Ph3PEtI
9
0
1
3d :
1:2:0.3 145
170
2
2
100 31 34 28
58 18f
e
1
1
CetyPy
100
5
3e:
1:2:0.5 145 3.5
100 28 39 25
BmImBF4
a
4
a : dibenzylamine; 5a : tribenzylamine; 6a : benzyl N-ben-
b
zylcarbamate (PhCH2NHCO2CH2Ph); Y: isolated yield of triben-
zylamine. Product purified by flash chromatography. Product
of tetrabutylphosphonium bromide (3b) (the molar ratio
c
d
13
2
2.
/1/3b was of 1:2.1:0.25). Results are reported in Table
e
purified by recrystallization. CetyPy: cetylpyridinium chloride
monohydrate. f Byproducts (10%).
Data show that under the investigated conditions
4
a and 5a ), sizable amounts (33-45%) of benzyl N-
amines 2b-d react quantitatively with DBnC to afford
the corresponding N,N-dibenzyl derivatives (5b-d ) in
comparable times (at 100-150 °C) and with isolated
yields in the range of 74-86%. Moreover, the selectivity
benzylphenylcarbamate (6a ) are observed. The overall
alkylation to carbamation selectivity (SA/C) does not
exceed 61%.12
The presence of a phosphonium salt has a dramatic
influence on the reaction rate and most importantly, on
the reaction selectivity. At 170 °C, when hexadecyltribu-
tylphosphonium bromide (3a ) is usedseven in a very low
amount (molar ratio 3a /2a ) 0.05; entry 2a)sthe conver-
sion is quantitative after only 2 h, and the alkylation
reaction takes over, yielding tribenzylamine as the
primary product (58%). The SA/C ratio is enhanced to 86%.
The catalytic effect is well evident for both compounds
SA/C is always very high (86-100%), especially in the case
of compounds 2d whose reaction, perhaps due to steric
reasons, does not show the formation of the corresponding
carbamate at all (entry 3).
In the case of compound 2e, benzyl 4-(N,N-dibenzyl-
aminomethyl)benzoate (5e) is obtained in a 85% isolated
(12) SA/C is defined as the ratio: ([4a ] + [5a ])/([4a ] + [5a ] + [6a ]) ×
1
00.
(
13) Under the conditions used for amines 2a -d , compound 2e was
3
a and 3b. For example, as the 3a :2a molar ratio is
not completely soluble. A higher amount of DBnC was used: the molar
increased from 0.05 to 0.3, the time for the complete
ratio 2e/1/3b was 1:3.5:0.25.
3
954 J . Org. Chem., Vol. 69, No. 11, 2004

F IGURE 1. (A) IR spectra of pure benzylamine (2a , black), pure tetrabutylphosphonium bromide (3b, blue), and a mixture of 2a
-
1
and 3b (red), recorded at room temperature. (B) enlargement of Figure 1A between 2600 and 4000 cm
.
TABLE 2. Rea ction of Alip h a tic Am in es (2b-d ) w ith
claveswhich is known to catalyze carbamate formation
a
DBn C (1) in th e P r esen ce of Bu 4P Br (3b)
16
even in trace amounts. This should also be helped by
1
7
the high solubility of CO
contrary, when reactions are performed in an open vessel
as for the case of DBnC), carbon dioxide can easily
2
in ionic liquids. On the
(
escape from the mixture so that alkylation takes place
almost exclusively.
P ossible Role of P h osp h on iu m Sa lts. In the reac-
tion of primary aliphatic amines with DBnC, data of
Tables 1 and 2 showed that the presence of a catalytic
amount of an onium salt, in particular of a phosphonium
type, had a 2-fold effect: (i) it dramatically improved the
rate and (ii) it favored a BAl2 mechanism. These observa-
tions implied that the effect of the salt had to involve
some kind of activation/interaction with the reagents 1
and 2. To investigate this, IR spectra of pure compounds
1, 2a , and 3b and of mixture thereof were recorded at
both ambient temperature and at 150 °C. Results are
reported in Figure 1.
a
All reactions were performed at 170 °C and at atmospheric
b
pressure: the molar ratio 2/1/3b was of 1:2:0.25. Y: isolated yield
of N,N-dibenzylated amine 5. Product purified by flash chroma-
tography; Product purified by distillation. nd: not determined.
c
d
e
SCHEME 3. Rea ction of Am in es w ith Dim eth yl
Ca r bon a te in Ion ic Liqu id s
The analysis of the N-H vibrational modes of benzyl-
amine shows a relevant feature. The pure amine displays
the two expected bands of asymmetrical and symmetrical
-
1
stretching modes at 3372 and 3303 cm , respectively
Figure 1, black curves), the latter being much less
(
yield (entry 4). The simultaneous esterification of the acid
1
8
intense. Instead, the IR spectrum of the mixture of
2
group (either with DBnC or the coproduct PhCH OH) is
reasonably catalyzed by the salt 3b:14 this reaction could
benzylamine and the salt 3b (red curve) shows that the
-
1
weaker band (at 3303 cm ) of the pure compound is no
longer present, and a new absorption peak appears at
not be avoided even when DBnC was used in less than 2
equiv with respect to the reagent 2e.
-
1
3
262 cm . Interestingly, the two bands at 3365 and 3262
It should be noted here that these results are distinctly
different from those reported for the similar reaction of
aliphatic amines with dimethyl carbonate in the presence
of ionic liquids: in that case in fact, working at 170 °C
in a sealed vessel (autoclave), only traces of methylation
-
1
cm possess the same intensity.
The evident shift to the right of a N-H stretching mode
of the amine, which is visible at both ambient tempera-
1
9
ture and at 150 °C (Figures 1B and 2, respectively),
reflects a possible acid-base interaction between the
amine and the phosphonium salt (Scheme 4).
products are observed and methyl urethanes are formed
with up to 99% selectivity (Scheme 3).15
Such a striking difference is most likely due to the
presence of small amounts of CO
petitive methylation reaction and confined in the auto-
2
sformed by the com-
(16) (a) Aresta, M.; Quaranta, E. Tetrahedron 1991, 47, 9489. (b)
Selva, M.; Tundo, P.; Perosa, A. Tetrahedron Lett. 2002 (43), 1217-
1
219. (c) Selva, M.; Tundo, P. Tetrahedron Lett. 2003 (44), 8139-8142.
(17) Blanchard, L. A.; Gu, Z.; Brennecke, J . F. J . Phys. Chem. B
(
14) Deng, Y. Q.; Shi, F.; Beng, J . J .; Qiao, K. J . Mol. Catal. A 2001,
65, 33-36.
15) Siam, T.; Guo, S.; Shi, F.; Deng, Y. Tetrahedron Lett. 2002, 43,
145-47.
2001, 105, 2437-2444.
1
(18) (a) http://webbook.nist.gov/. (b) Silverstein, R. M.; Bassler, G.
C.; Morrill, T. C. Spectrometric Identification Of Organic Compounds,
5th ed.; Wiley: J ., & Sons: New York, 1991; pp 123-124.
(
8
J . Org. Chem, Vol. 69, No. 11, 2004 3955

phatic amines with dibenzyl carbonate as an alkylating
agent. Although the reaction is quite energy intensive,
it shows valuable synthetic and environmentally benign
features: (i) DBnC allows the replacement of toxic benzyl
halides and avoids the use of stoichiometric amount of
base, (ii) the reaction takes place under solventless
conditions, and (iii) a high alkylation selectivity is
observed providing that a phosphonium salt be present
as a catalyst. Under these conditions, a preliminary
reaction of an amino acidic substrate, indicates that the
N-alkylation cannot be discriminated over the esterfica-
tion of the acid functionality. IR data suggest that the
role of the salt on the reaction outcome is primarily
played through an interaction with the amine, while no
effects seem to involve the organic carbonate.
Exp er im en ta l Section
Reactions were carried out with the following procedure: a
mixture of the amine (2a -e, 8.5 mmol) and DBnC (17.9 mmol
for 2a -d ; 31.4 mmol for 2e, see ref 13) was loaded in a 10-mL
glass reactor (shaped as a test tube) equipped with condenser,
a magnetic bar, and a side screw-capped neck for the withdrawal
of samples. To this mixture, a salt of onium- or imidazolium-
type (3a , hexadecyltributylphosphonium bromide; 3b , tetra-
butylphosphonium bromide; 3c, ethyltriphenyl phosphonium
iodide; 3d , cetylpyridinium chloride; 3e, 1-butyl-3-methyl-
imidazolium tetrafluoroborate) was added (.0.05 to 0.5 molar
equiv with respect to 2a ; see Tables 1 and 2). The reactor was
then dipped in an oil bath preheated at the desired temperature
F IGURE 2. IR spectrasenlarged between 2600 and 4000
-1
cm sof pure benzylamine (2a , black) and a mixture of 2a and
b (red), recorded at 150 °C.
3
2
SCHEME 4. In ter a ction s betw een th e NH Gr ou p
of Ben zyla m in e a n d a Tetr a a lk ylp h osp h on iu m
a
Br om id e
(145-170 °C), with stirring. At intervals, samples of the reaction
mixture were withdrawn and analyzed by GC and GC/MS.
The same procedure was also used for the reaction of 2a with
DBnC in the absence of the onium salt. In all cases, no additional
solvents or co-solvents were employed.
Products 5a -e were isolated either by flash-chromatography
1
or recrystallization/distillation, and characterized by GC/MS, H
NMR, and 13C NMR.
Further details on the reaction methodology, and on the
isolation and characterization of products 5a -e, are described
in the Supporting Information.
Spectroscopic and physical properties were in agreement with
those reported in the literature. 5a : mp 90-92 °C (white solid)
2
1
21
[
0
lit. mp 91-93 °C]. 5b: colorless liquid [lit. bp 180-185 °C/
2
2
.5 mm]. 5c: colorless liquid [lit. bp 216-217 °C/0.5 mm]. 5d :
22
mp 64-67 °C (white solid). Product 5e was a highly viscous
oil.
Ack n ow led gm en t. MIUR (Italian Ministry of Uni-
versity and Research) and INCA (Interuniversity Con-
sortium Chemistry for the Environment) are gratefully
acknowledged for financial support. Mr. Alessandro
Baldan is also acknowledged for his help with IR
spectra.
Su p p or t in g In for m a t ion Ava ila b le: 1H and 13C NMR
and GC/MS spectra for N,N-dibenzylamines 5a -d . This ma-
terial is available free of charge via the Internet at
http://pubs.acs.org.
a
b : alkyl substituent.
2
The increased steric hindrance around the NH group
would plausibly facilitate the attack of the nucleophile
on the alkyl rather than the carbonyl terminus of the
organic carbonate 1. The high reaction selectivity (SA/C
)
could be explained accordingly. On the same basis
however, a clear reason for the enhancement of the
reaction rate cannot be presently accounted for.
It is noteworthy that a deformation of the OH stretch-
ing mode of phenol has also been reported in the IR
J O049840C
+
- 20
(19) Probably because of the increase of the temperature, the NH-
analysis of a mixture of phenol and n-Bu
4
N Br .
-1
adsorption maxima of Figure 1B (25 °C: 3365 and 3262 cm ) are
By contrast, the IR spectrumsnot shownsof the
mixture of the carbonate 1 and the salt 3b is merely the
overlap of the IR spectra of the pure compounds, sug-
gesting that the lack of any specific interaction between
the two moieties.
slightly different from the corresponding ones of Figure 2 (150 °C: 3375
and 3278 cm- ).
1
(
20) Ouk, S.; Thiebaud, S.; Borredon, E.; Le Gars, P. Appl. Catal.
2
003, 241, 227-233.
(21) Katritzky, A. R.; Yannakopoulou, K.; Lue, P.; Rasala, D.; Urogdi,
L. J . Chem. Soc., Perkin Trans. 1 1989, 225-233.
(22) Lutz, R. E.; Bailey, P. S.; Rowlett, R. J .; Wilson, J . W.; Allison,
The reaction here described is a new and direct
methodology for the N,N-dibenzylation of primary ali-
R. K.; Clark, M. T.; Leake, N. H.; J ordan, R. J . Keller, R. J .; Nicodemus,
K. C. J . Org. Chem. 1947, 12, 760-3.
3
956 J . Org. Chem., Vol. 69, No. 11, 2004