Direct, one-pot reductive alkylation of anilines with functionalized acetals mediated by triethylsilane and tfa. straightforward route for unsymmetrically substituted ethylenediamine

Article abstract of DOI:10.1021/jo102109f

A new, robust, and reliable method has been developed for the selective reductive N-alkylation of primary and secondary aromatic amines with some functionalized acetals using TFA/Et₃SiH as a reagent combination. A variety of unsymmetrically sub

Full text of DOI:10.1021/jo102109f

pubs.acs.org/joc
Direct, One-Pot Reductive Alkylation of Anilines
with Functionalized Acetals Mediated by
Triethylsilane and TFA. Straightforward Route for
Unsymmetrically Substituted Ethylenediamine
Marika Righi, Annalida Bedini, Giovanni Piersanti,*
Federica Romagnoli, and Gilberto Spadoni
FIGURE 1. General structure of N-diarylaminoalkylamides and
two representative melatonin ligands.
Department of Drug and Health Sciences,
University of Urbino “Carlo Bo”, Piazza del Rinascimento 6,
61029 Urbino (PU), Italy
UCM765 (4a) and UCM924 (4b) were required in multigram
quantities to fulfill preclinical development needs.3
Many compounds of pharmaceutical interest have a dia-
rylalkylidendiamine scaffold, so it is of great interest to
develop a general, practical, and efficient synthetic proce-
dure to access these substances. It is clear that, wherever
possible, it would be desirable to find a step-economical
synthesis4 that does not involve the use of protecting groups5
and expensive or toxic reagents. Despite the apparent sim-
plicity of the ethylenediamine structure, there are few effi-
cient and selective methods currently available for their
preparation. One of the more direct approaches provides for
the alkylation of an amine with highly toxic substituted azir-
idines or their precursors such as N,N-disubstituted chloro-
ethylamines.6 On the contrary, 2-oxazolines7a and 2-oxazo-
lidinones7b can be viewed as less toxic synthetic equivalents
of aziridines. Therefore, direct nucleophilic ring-opening at
the 5-position of oxazolines with a secondary amine to give
β-substituted ethylcarboxamides seemed more attractive.
However, in our hands, no more than 34% yield was achieved
giovanni.piersanti@uniurb.it
Received October 25, 2010
A new, robust, and reliable method has been developed
for the selective reductive N-alkylation of primary and
secondary aromatic amines with some functionalized
acetals using TFA/Et3SiH as a reagent combination. A
variety of unsymmetrically substituted ethylenediamines
can be synthesized in a one-pot procedure in excellent
yields at room temperature. This new procedure offers
significant advantages over previous synthetic approaches,
including brevity, mild reaction conditions, excellent yields,
and high functional group tolerance.
€
using different diarylamines and Bronsted acids at 180 °C
(Figure 2, approach A).
Alternatively, the desired unsymmetrically substituted
ethylendiamines can also be achieved in a multistep se-
quence. For example, N-acylation with toxic chloroace-
tylchloride followed by reduction of the amide group,
phthalimide alkylation and final deprotection is one strat-
egy. The same product can be obtained in a two-step
procedure by N-cyanoalkylation with bromoacetonitrile (in
the presence of a strong base) followed by reduction of the
nitrile (Figure 2, approach B).2,8 However, these approaches
afforded very low overall yields and were considered not
feasible for the preparation of arrays of compounds due
to the harsh reducing conditions, security issues, and low
functional group tolerance.
In support of an ongoing medicinal chemistry research
program in the melatonin field1 aimed at the discovery of
new treatments for insomnia, there was a need for developing
a safe and scalable synthetic process to supply a number
of N-diarylaminoalkylamides 1, a subclass of unsymmetri-
cally substituted ethylenediamines (Figure 1).2 In particular,
(1) For recent examples, see: (a) Mor, M.; Rivara, S.; Pala, D.; Bedini, A.;
Spadoni, G.; Tarzia, G. Expert Opin. Ther. Pat. 2010, 8, 1059–1077. (b)
Lucarini, S.; Alessi, M.; Bedini, A.; Giorgini, G.; Piersanti, G.; Spadoni, G.
Chem. Asian J. 2010, 3, 550–554. (c) Spadoni, G.; Bedini, A.; Diamantini, G.;
Tarzia, G.; Rivara, S.; Lorenzi, S.; Lodola, A.; Mor, M.; Lucini, V.;
Pannacci, M.; Caronno, A.; Fraschini, F. ChemMedChem 2007, 12, 1741–
1749.
(2) (a) Rivara, S.; Vacondio, F.; Fioni, A; Silva, C.; Carmi, C.; Mor, M.;
Lucini, V.; Pannacci, M.; Caronno, A.; Scaglione, F.; Gobbi, G.; Spadoni,
G.; Bedini, A.; Orlando, P.; Lucarini, S.; Tarzia, G. ChemMedChem 2009, 10,
1746–1755. (b) Rivara, S.; Lodola, A.; Mor, M.; Bedini, A.; Spadoni, G.;
Lucini, V.; Pannacci, M.; Fraschini, F.; Scaglione, F.; Sanchez, R. O.; Gobbi,
G.; Tarzia, G. J. Med. Chem. 2007, 26, 6618–6626.
(4) (a) Wender, P. A.; Handy, S. T.; Wright, D. L. Chem. Ind. 1997, 765–
769. (b) Wender, P. A.; Verma, V. A.; Paxton, T. J.; Pillow, T. H. Acc. Chem.
Res. 2008, 41, 40–49. (c) Wender, P. A.; Miller, B. L. Nature 2009, 460,
197–201.
(5) (a) Young, I. S.; Baran, P. S. Nat. Chem. 2009, 1, 193–205. (b) Baran,
P. S.; Maimone, T. J.; Richter, J. M. Nature 2007, 446, 404–408.
(6) (a) Dermer, O. C.; Ham, G. E. Ethylenimine and other Aziridines;
Academic Press: New York, 1969; pp 237-239. (b) Ibanez, C. An. Quim.
1974, 70, 733.
(7) (a) Fazio, M. J. J. Org. Chem. 1984, 49, 4889–4993. (b) Poindexter,
G. S.; Donald, A. O.; Dolan, P. L.; Woo, E. J. Org. Chem. 1992, 57, 6257–
6265.
(8) Lucini, V.; Pannacci, M.; Scaglione, F.; Fraschini, F.; Rivara, S.; Mor,
M.; Bordi, F.; Plazzi, P. V.; Spadoni, G.; Bedini, A.; Piersanti, G.; Diaman-
tini, G.; Tarzia, G. J. Med. Chem. 2004, 17, 4202–4212.
(3) Gobbi, G.; Mor, M.; Rivara, S.; Fraschini, F.; Tarzia, G.; Spadoni,
G.; Bedini, A.; Lucini, V. WO 2007079593 A1, 2007.
704 J. Org. Chem. 2011, 76, 704–707
Published on Web 12/22/2010
DOI: 10.1021/jo102109f
r
2010 American Chemical Society

Righi et al.
JOCNote
these disappointing results, we still believed that hydro-
€
silanes in the presence of a strong Bronsted acid such as TFA
should be effective for our purposes.12 Indeed, when triethylsi-
lane (2.5 equiv) was added to a solution containing 3-methoxy-
N-phenylaniline (2a) (1.0 equiv) and N-(2,2-dimethoxy-
ethyl)acetamide (3a) (1.4 equiv) in CH2Cl/TFA (2:1), the
desired tertiary amine UCM765 (4a) was formed smoothly.13
In 2 h at room temperature, the reaction was complete and
the product 4a was isolated in 93% yield (Table 1, entry 1).
The same reaction conditions when applied to 3-bromo-N-(4-
fluorophenyl)aniline (2b) gave the alkylated product UCM924
(4b) in excellent yield (Table 1, entry 2). It is also worth noting
that debrominated side product was not detected by LC-MS
in the crude mixture, demonstrating that these reaction condi-
tions are mild and selective. A number of other diarylamines
having therapeutically relevant scaffolds (2c-f) were tested
with this new method (Table 1, entries 3-6). The biological
activity manifested by tricyclic, nitrogen containing heterocyc-
lic compounds makes them attractive substrates to test the
reaction. Thus, dibenzazepine 2c, dihydrodibenzazepine 2d,
carbazole 2e, and phenothiazine 2f were subjected to the above
reductive N-alkylation conditions, and the corresponding
N-alkylated products 4c-f were obtained in high yields
(85-95%). Notably, 2d reacted readily and in high yield under
these reaction conditions, while no reaction has been reported
under standard reductive amination conditions even with
aldehydes.10 In certain instances, the reductively alkylated
products could be directly crystallized in high purity following
aqueous workup. When the products were oils, chromato-
graphy was necessary to obtain analytically pure material. In
general, however, the crude products from these reductive
alkylations were sufficiently clean that a short filtration was
enough to have analytically pure product. We then explored
reductive N-alkylation reactions of N-(2,2-dimethoxyethyl)-
acetamide with different N-alkylanilines, as illustrated in
Table 1 (entries 7-11), including some partially saturated
bicyclic heterocycles such as indoline and tetrahydroquinoline
(entries 7 and 8); all reacted smoothly to generate the desired
products in good to excellent yields. It is noteworthy to observe
that 4-nitro-N-methylaniline (2j), underwent successful alkyla-
tion (95% yield), with no reduction of the nitro group, further
highlighting the remarkable chemoselective character of the
reducing system (Table 1, entry 10). Unfortunately, no reaction
occurred when N-isopropylaniline was used (Table 1, entry 11),
whereas an acceptable yield was obtained when the carbamate
was used as the amine partner (Table 2 entry 7). Having secured
access to a range of tertiary amines, attention was focused on
the application of the same conditions to primary anilines.
It was found that anilines bearing both electron-with-
drawing groups (nitro, ester, or cyano) and/or electron-
donating groups were alkylated smoothly in high yields
(Table 2) with functional groups such as NO2, CF3, CO2Me,
FIGURE 2. Possible approaches to unsymmetrically substituted
ethylenediamines.
Direct reductive amination of carbonyl compounds has
been widely utilized to prepare amines and offers compelling
advantages over other syntheses, including brevity, wide
commercial availability of substrates, generally mild reac-
tion conditions, high functional group tolerance, ease of
operation, and cost effectiveness. However, reductive ami-
nation of poorly reactive, electron-deficient arylamines is
known to be difficult. Recent work9 has shown the synthesis
of some ethylendiamines by reductive N-alkylation of sui-
table primary or secondary N-alkylanilines with commer-
cially available N-Boc glycinal, but there are no reports of
this protocol using diarylamines as the amine partner
(Figure 2, approach C). Indeed, our initial efforts to prepare
UCM765 (4a) by reacting the diarylamine 2a with the
commercially available N-Boc glycinal using NaBH(OAc)3
or NaCNBH3 were thwarted by insufficient imine/iminium
concentration and competing direct reduction of the carbo-
nyl group. Even with excess aldehyde, conversion of the
amine remained below 10%. The standard literature recom-
mendation for poorly nucleophilic amines is to add acetic
acid, along with a concomitant increase in the amounts of
carbonyl component and reducing agent.10 In the present
case, poor yields were still obtained with addition of AcOH,
although a trend toward increasing yield with increasing
quantities of acid was clear. Instead, the same protocol
applied to N-methylaniline (2i) provided the alkylated pro-
duct in modest yield (ca. 30%).
Decaborane11a and a polymethylhydrosiloxane (PMHS)/
TFA combination system11b have been recently used for the
successful one-pot reductive amination of benzaldehyde
dimethyl acetal with primary aromatic amines. Therefore,
we evaluated the possibility of extending these methodol-
ogies to diarylamine 2a with the functionalized acetal N-(2,2-
dimethoxyethyl)acetamide (3a).
While using decaborane no reaction occurred, using
PMHS and TFA in CH2Cl2 at room temperature, the
desired product was obtained in very poor yields. Despite
(9) (a) Chambers, L. J.; Collis, K. L; Dean, D. K.; Munoz-Muriedas, J.;
Steadman, J. G. A.; Walter, D. S. WO 2009053459 A1, 2009. (b) Cho, Y. L.;
Song, H, Y.; Lee, D. Y.; Baek, S. Y.; Chae, S. E.; Jo, S. H.; Kim, Y. O.; Lee,
H. S.; Park, J. H.; Park, T. K.; Woo, S. H.; Kim, Y. Z. WO 2008140220 A1,
2008. (c) Chen, X.; Cioffi, C. L.; Dinn, S. R.; Escribano, A. M.; Fernandez,
M. C.; Fields, T.; Herr, R. J.; Mantlo, N. B.; De la Nava, E. M. M.; Mateo-
Herranz, A. I.; Parthasarathy, S.; Wang, X. WO 2006002342 A1, Jan 5, 2006.
(d) Halim, M.; Tremblay, M. S.; Jockusch, S.; Turro, N. J.; Sames, D. J. Am.
Chem. Soc. 2007, 129, 7704–7705. (e) Hamilton, A.; Buckner, F.; Glenn, M.;
Van Voorhis, W. WO 2006102159 A2, 2006.
(12) For reviews on reductions using hydrosilanes, see: (a) Kursanov,
D. N.; Parnes, Z. N.; Loim, N. M. Synthesis 1974, 633. (b) Nagai, P. Org.
Prep. Proc. Int. 1980, 12, 13. (c) Guizzetti, S.; Benaglia, M. Eur. J. Org. Chem.
2010, 5529–5541.
(13) For other use of the triethylsilane in reducing reactions, see: (a)
ꢀ
Dube, D.; Scholte, A. A. Tetrahedron Lett. 1999, 40, 2295–2298. (b) Lee,
(10) (a) Abdel-Magid, A. F.; Carson, K. G.; Harris, B. D.; Maryanoff,
C. A.; Shah, R. D. J. Org. Chem. 1996, 61, 3849–3862. (b) Abdel-Magid,
A. F.; Mehrman, S. J. Org. Process Res. Dev. 2006, 10, 971–1031.
(11) (a) Park, E. S.; Lee, J. H.; Kim, S. J.; Yoon, C. M. Synth. Commun.
2003, 33, 3387–3396. (b) Patel, J P.; Li, A.; Dong, H.; Korlipara, V. L.;
Mulvihill, M. J. Tetrahedron Lett. 2009, 50, 5975–5977.
O.-Y.; Law, K.-L.; Ho, C.-Y.; Yang, D. J. Org. Chem. 2008, 73, 8829–8837.
(c) Mizuta, T.; Sakaguchi, S.; Ishii, Y. J. Org. Chem. 2005, 70, 2195–2199. (d)
Lucarini, S.; Bedini, A.; Spadoni, G.; Piersanti, G. Org. Biomol. Chem. 2008,
6, 147–150. For an elegant study demonstrating that organosilanes are
weaker hydride donors, see: Richter, D.; Mayr, H. Angew. Chem., Int. Ed.
2009, 48, 1958–1961.
J. Org. Chem. Vol. 76, No. 2, 2011 705

Righi et al.
JOCNote
TABLE 1. Reductive N-Alkylation of Secondary Anilines with
TABLE 2. Reductive N-Alkylation of Primary Anilines and
N-(2,2-Dimethoxyethyl)acetamidea
Benzylcarbamate with N-(2,2-Dimethoxyethyl)acetamidea
aAll reactions were performed at room temperature for 2 h with 1.1
equiv of acetal, 1.0 equiv of amine, and 2.5 equiv of Et3SiH in CH2Cl2/
TFA 2:1 (0.25 M). bIsolated yields. c16 h at room temperature.
poor nucleophilicity and/or steric inaccessibility, such as
2,4-dinitro- and 2,4,6-trichloroanilines react either very
slowly or show no reaction under the standard reductive
amination conditions.10 On the contrary, these weakly basic
anilines when subjected under our conditions provided the
desired amides 4q and 4p in good yields. The ability to use
primary aromatic amines under these acid-promoted condi-
tions is notable since the competitive reactions involving the
resulting secondary amines and the starting carbonyl/acetal
has been reported to be a significant issue. Having demon-
strated that both primary and secondary anilines undergo
reductive N-alkylation with acetamidoacetaldehyde dimethyl
acetal, we then briefly investigated different functionalized
acetals (Table 3). The results for reductive N-alkylation of
the pharmaceutically widely used 5H-dibenzo[b, f ]azepine
scaffold with different functionalized acetals are shown in
Table 3. The readily available superior homologue of 3a and
acetal 3c both reacted very well, even though a longer reaction
aAll reactions were performed at room temperature for 2 h with 1.4
equiv of acetal, 1.0 equiv of amine, and 2.5 equiv of Et3SiH in CH2Cl2/
TFA 2:1 (0.25 M). bIsolated yields. c16 h at room temperature. dNR: no
reaction.
Cl, CN, OCH3, HNCOCH3, and double bonds remaining
unaffected. Furthermore, the results in Table 2 show that this
procedure performs well also in cases that caused difficulties
for other reductive amination. In particular, substrates with
706 J. Org. Chem. Vol. 76, No. 2, 2011

Righi et al.
JOCNote
TABLE 3. Reductive Amination with Various Acetals of
5H-Dibenzo[b, f ]azepine
relevance of this substructure should render this approach
broadly useful.
Experimental Section
General Procedure for the Preparation of Unsymmetrically
Substituted Ethylenediamines. To a solution of suitable aniline
(1 mmol) and acetal (1.4 mmol) in CH2Cl2 (2 mL) under
nitrogen were added TFA (1 mL) and triethylsilane (TES, 2.5
mmol), and the resulting mixture was stirred at room tempera-
ture. The reaction was cooled at 0 °C, carefully neutralized with
a saturated solution of NaHCO3, and diluted with CH2Cl2. The
two phases were separated and the aqueous layer was extracted
with CH2Cl2 (3ꢀ10 mL). The combined organic phases were
washed with brine, dried over Na2SO4, filtered, and concentra-
ted under reduced pressure. The resulting residue was purified
by flash chromatography on silica gel using cyclohexane/ethyl
acetate as the eluent.
entry
Z
time (h)
product
yielda (%)
1
2
3
4
5
-NHCOCH3 (3a)
-CH2NHCOCH3(3b)
-CN (3c)
-NHCOCF3 (3d)
-NH2 (3e)
2
16
16
2
4a
4s
95
71
4t
4u
60
85
48
4vb
NRc
aIsolated yields. bAmine 4v was obtained by hydrolysis of 4u with
potassium carbonate in methanol. cNR: no reaction.
time was needed (Table 3, entries 2 and 3) demonstrating that
this approach can be easily applied to the synthesis of unsym-
metrical propylenediamines. Under these optimized condi-
tions, no alkylation occurred with 2,2-dimethoxyethanamine.
However, the reaction was successful when the free amino
group was protected with the easily cleavable trifluoroacetyl
group (Table 3, entry 4). In addition to the alkylation pro-
ceeding almost quantitatively, the removal of the trifluoro-
acetyl group was extremely simple affording the unsymme-
trical ethylenediamine with a free amino group ready for further
functionalization, in very high yield (Table 3, entry 5).
In summary, an expedient method for the synthesis of
unsymmetrically substituted ethylene and propylendiamine
is described. An effective and highly chemoselective proce-
dure was developed for the reductive N-alkylation of pri-
mary and secondary aniline substrates with different func-
tionalized acetals normally viewed as poor partners in this
process. Under these conditions, there is no requirement for
a large excess of either the acetal partner or the reducing
agent and the conditions are mild enough to tolerate func-
tionalities such as nitro, cyano, ester, double bonds, and
halogens. Taken as a whole, the described chemistry outlines
a method by which a range of functionalized diamines cores
can be rapidly accessed in high yield starting from inexpensive
materials with minimal purification. In addition, it provides a
convenient alternative to the reported synthesis of substituted
ethylenediamines based on aziridine, phthalimide alkyla-
tion, or nitrile reduction. The ubiquity of ethylenediamines
in natural products combined with the pharmaceutical
(Z)-N-(2-(5H-Dibenzo[b,f]azepin-5-yl)ethyl)acetamide, 4c. The
general method using 5H-dibenzo[b,f]azepine (193 mg, 1.0 mmol)
gave after chromatographic purification 4c (264 mg, 0.95 mmol)
as a yellowish solid: yield 95%; mp 127-128 °C; MS (ESI) 279.1
[M þ 1]; IR (film, cm-1) 3262,1635,1570; 1H NMR (CDCl3, 200
MHz): δ 1.88 (s, 3H), 3.38 (dd, 2H, J=5, 5.5 Hz), 3.89 (t, 2H, J=
5.5 Hz), 6.05 (br s, 1H), 6.81 (s, 2H), 6.99-7.33 (m, 8H); 13C
NMR (CDCl3, 50 MHz) δ 170.0, 149.6, 133.9, 132.0, 129.3, 129.2,
124.0, 120.6, 49.6, 36.5, 23.3. Anal. Calcd for C18H18N2O
(278.14): C, 77.67; H, 6.52; N, 10.06. Found: C, 77.71; H, 6.54;
N, 10.09.
Methyl 2-(2-Acetamidoethylamino)benzoate, 4n. The general
method using methyl 2-aminobenzoate (151 mg, 129 μL, 1.0
mmol) gave after chromatographic purification 4n (229 mg, 0.97
mmol) as a white solid: yield 97%; mp 107-108 °C (ether); MS
(ESI) 237.1 [M þ 1]; IR (film, cm-1) 3251, 1734, 1667; 1H NMR
(CDCl3) δ 1.99 (s, 3H), 3.41-3.52 (m, 4H), 3.86 (s, 3H), 5.90
(brs, 1H), 6.66 (dd, 1H, J=6, 7 Hz), 6.79 (dd, 1H, J=6, 7 Hz),
7.33 (dd, 1H, J=7 Hz), 7.80 (brs, 1H), 7.90 (dd, 1H, J=6, 7 Hz);
13C NMR (acetone d6) δ 169.5, 168.5, 151.1, 134.6, 131.4, 114.4,
111.3, 109.9, 50.8, 41.9, 38.4, 22.0; Anal. Calcd for C12H16N2O3
(236.1): C, 61.00; H, 6.83; N, 11.86. Found: C, 61.06; H, 6.81; N,
11.81.
Acknowledgment. This work was supported by grants
ꢀ
from the Italian Ministero dell’Universita e della Ricerca
and University of Urbino “Carlo Bo”.
Supporting Information Available: Experimental proce-
dures along with copies of spectra. This material is available
free of charge via the Internet at http://pubs.acs.org.
J. Org. Chem. Vol. 76, No. 2, 2011 707