Cesium Hydroxide Promoted Chemoselective N-Alkylation for the Generally Efficient Synthesis of Secondary Amines

Article abstract of DOI:10.1021/ol9910417

(Matrix presented) Selective N-alkylation of primary amines was developed using cesium hydroxide to prepare various secondary amines efficiently. A cesium base not only promoted monoalkylations of primary amines but also suppressed overalkylations. Various amines and alkyl bromides were examined, and the preliminary results demonstrated this methodology was highly chemoselective, favoring mono-N-alkylation over dialkylation. In particular, use of amino acid derivatives afforded the desired secondary amines exclusively.

Full text of DOI:10.1021/ol9910417

ORGANIC
LETTERS
1999
Vol. 1, No. 12
1893-1896
Cesium Hydroxide Promoted
Chemoselective N-Alkylation for the
Generally Efficient Synthesis of
Secondary Amines
Ralph N. Salvatore, Advait S. Nagle, Shaun E. Schmidt, and Kyung Woon Jung*
Department of Chemistry (CHE 305), UniVersity of South Florida, and Drug
DiscoVery Program, H. Lee Moffitt Cancer Center & Research Institute,
4202 E. Fowler AVenue, Tampa, Florida 33620-5250
kjung@chuma.cas.usf.edu
Received September 13, 1999
ABSTRACT
Selective N-alkylation of primary amines was developed using cesium hydroxide to prepare various secondary amines efficiently. A cesium
base not only promoted monoalkylations of primary amines but also suppressed overalkylations. Various amines and alkyl bromides were
examined, and the preliminary results demonstrated this methodology was highly chemoselective, favoring mono-N-alkylation over dialkylation.
In particular, use of amino acid derivatives afforded the desired secondary amines exclusively.
Secondary amines, which are widely utilized in various fields,
are important in many organic syntheses.1 The synthetic
approaches to secondary amines from primary amines include
reductive alkylation,2 the use of protecting groups,3 and direct
N-alkylation.4 However, these methods are limited in ap-
plication because of concomitant overalkylations to tertiary
amines and quartenary ammonium salts. While reductive
alkylation is known to be a reliable method, it is often
accompanied by overalkylation.2a Traditional methods typi-
cally use protecting groups during amine alkylations by
routes which require lengthy sequences.
Direct N-alkylation techniques are also inefficient due to
overalkylations, and the most practical method is to use a
large excess of an amine, which is often expensive. Over-
alkylations are still observed to a considerable extent under
these conditions. In an effort to circumvent this chronic
problem, we embarked on a cesium hydroxide mediated
N-alkylation procedure, which exhibited enhanced chemo-
selectivities in amine alkylations compared to the previously
reported protocols.
In our laboratories, Williamson-type ether synthesis was
investigated in the presence of cesium hydroxide and
tetrabutylammonium iodide to prepare various aliphatic
ethers efficiently.5 As delineated in Scheme 1, the represen-
(1) (a) Mitsunobu, O. In ComprehensiVe Organic Synthesis; Trost, B.
M., Fleming, I., Eds.; Pergamon: London, 1991; Vol. 6, p 65. (b) Gibson,
M. S. In The Chemistry of the Amino Group; Patai, S., Ed.; Interscience
Publishers: New York, 1968; p 37. (c) Sandler, S. R.; Karo, W. In Organic
Chemistry; Wasserman, H. H., Ed.; Academic Press: San Diego, 1983;
Vol. 12, p 377.
(2) (a) Szardenings, A. K.; Burkoth, T. S.; Look, G. C.; Campbell, D.
A. J. Org. Chem. 1996, 61, 6720 and references therein. (b) Pillai, R. B. C.
J. Mol. Catal. 1993, 84, 125. (c) Gribble, G. W.; Nutaitis, C. F. Synthesis
1987, 709. (d) Gribble, G. W.; Jasinski, J. M.; Pellicone, J. T.; Panetta, J.
A. Synthesis 1978, 766. (e) Marchini, P.; Liso, G.; Reho, A. J. Org. Chem.
1975, 40, 3453. (f) Rische, T.; Kitsos-Rzychon, B.; Eilbracht, P. Tetrahedron
1998, 54, 2723.
(4) (a) Spialter, L.; Pappalardo, J. A. In The Acyclic Aliphatic Tertiary
Amines; The Macmillan Company: New York, 1965; p 14. (b) O’Meara,
J. A.; Gardee, N.; Jung, M.; Ben, R. N.; Durst, T. J. Org. Chem. 1998, 63,
3117. (c) Koh, K.; Ben, R. N.; Durst, T. Tetrahedron Lett. 1993, 34, 4473.
(d) Valot, F.; Fache, F.; Jacquot, R.; Spagnol, M.; Lemaire, M. Tetrahedron
Lett. 1999, 40, 3689. (e) Suga, K.; Watanabe, S.; Fujita, T.; Pan, T. P.
Bull. Chem. Soc. Jpn. 1969, 42, 3606.
(3) (a) Phanstiel, IV, O.; Wang, Q. X.; Powell, D. H.; Ospina, M. P.;
Leeson, B. A. J. Org. Chem. 1999, 64, 803. (b) Croce, P. D.; La Rosa, C.;
Ritieni, A. J. Chem. Research (S) 1988, 346.
10.1021/ol9910417 CCC: $18.00 © 1999 American Chemical Society
Published on Web 11/16/1999

a greater selectivity of 9/1 in preference for the monoalkyl-
ation product 4. It was apparent that an unprecedented
“cesium effect” in N-alkylation was observed as seen in
O-alkylation.7
Scheme 1
Interestingly, the next comparative study implied that the
cesium base not only promoted N-alkylation of primary
amines, but also inhibited the formation of tertiary amines.
As illustrated in Scheme 2, the intended alkylation of
Scheme 2
tative example demonstrates the mild conditions for the
preparation of ether 2. Subsequently, we applied this technol-
ogy to N-alkylation, anticipating high chemoselectivity. With
the use of the amine as a limiting reagent, N-alkylation of
phenethylamine (3) with 1-bromobutane was conducted to
probe the optimal reaction conditions, under which secondary
amine 4 was produced in high yield. Observed selectivity
between mono- and dialkylations (9:1, respectively) was
superior to existing methods.1 It was also found that dry
powdered 4 Å molecular sieves accelerated the alkylation
by removal of water from the reaction media.6 Overall, the
reaction was remarkably facile and selective compared to
the known conditions.
Among the cesium bases examined, cesium hydroxide
monohydrate, in general, gave the highest yields and
selectivities although cesium carbonate also worked well,
depending on substrates.6 To confirm the possible cesium
effect, defined by the enhanced reactivities in the presence
of cesium salts,7 comparative studies between cesium bases
and other bases were performed, demonstrating that cesium
hydroxide was superior to other alkali bases tried with the
regard to the observed chemoselectivities. As depicted in
Table 1, other alkali hydroxides produced moderate yields
secondary amine 4 was very sluggish under our conditions,
affording the tertiary amine 5 in only 10% yield, whereas
72% of 5 was obtained along with the recovery of 25% of
4 in absence of cesium hydroxide after the same duration.
Under our cesium base promoted N-alkylation conditions,
primary and secondary amines exhibited opposing reactivi-
ties, suggesting that the improvement of chemoselectivity
would stem mainly from the retarded overalkylation or
reversal of normally observed alkylation rates.8
When various solvents were examined, N,N-dimethyl-
formamide was found to be the solvent of choice as
represented in Table 2. Several solvents such as dimethyl
Table 2. Use of Various Solvents in Cesium Base Promoted
N-Alkylation of 3
Table 1. N-Alkylation Utilizing Different Bases
sulfoxide, 1-methyl-2-pyrrolidinone, and N,N-dimethyl-
acetamide were comparable to DMF in terms of the yields
of 4 and the selectivities of 4 over 5. It is worthy to mention
that high chemoselectivity was observed regardless of solvent
choice. On the contrary, the reactions were sluggish in most
other solvents including acetonitrile and dichloromethane.
Next, various bromides and amines were subjected to
N-alkylations under the standard conditions to evaluate the
efficiency and the chemoselectivity in general.
of the desired product along with a considerable amount of
the tertiary amine 5, whereas cesium hydroxide allowed for
(5) For our O-alkylations, see: (a) Dueno, E. E.; Chu, F.; Kim, S.-I.;
Jung, K. W. Tetrahedron Lett. 1999, 40, 1843. (b) Chu, F.; Dueno, E. E.;
Jung, K. W. Tetrahedron Lett. 1999, 40, 1847. (c) Kim, S.-I.; Chu, F.;
Dueno, E. E.; Jung, K. W. J. Org. Chem. 1999, 64, 4578. (d) Parrish, J. P.;
Sundaresan, B.; Jung, K. W. Synth. Commun. 1999, 29, 4423.
(6) When molecular sieves were not activated, yields and selectivities
diminished. Further studies on optimization of reaction conditions will be
subject to future publication in the format of a full paper.
(7) Galli, C. Org. Prep. Proced. Int. 1992, 24, 287 and references therein.
Org. Lett., Vol. 1, No. 12, 1999
1894

As demonstrated in Table 3, the newly developed tech-
niques were compatible with various bromides, both active
mono-N-alkylated product 6. Unhindered primary bromides
still bestowed high chemoselectivities compared to the
previously reported methods.
Similar trends were noted in varying amines as shown in
Table 4. Primary and secondary alkyl groups offered
Table 3. N-Alkylation using Various Bromides
Table 4. N-Alkylation using Various Amines
and unreactive. Unreactive bromide such as 8 and active
bromides including benzyl and allyl bromides gave similar
results9 to the standard reaction shown in Scheme 1 while
N-alkylation with active halides proceeded efficiently with
use of a catalytic amount of cesium hydroxide. Introduction
of a small degree of sterics such as an isobutyl moiety gave
rise to the exclusive synthesis of the monoalkylation product
in good yield (entry 4). Secondary bromides also led to the
exclusive formation of secondary amines as expected (entries
5 and 6). Keeping the theme of peptidomimetics and chiral
auxiliaries in mind, amino bromides10 such as 9 and 10 were
subjected to our conditions, successfully affording the desired
N-alkylation products without concomitant production of the
overalkylated products.9
secondary amines 11 as major products (entries 1-4),
whereas sterically demanding aliphatics furnished the desired
products exclusively (entries 5-8). CsOH promoted N-
alkylations of sterically hindered amines were facile and
pragmatic, whereas the known methodologies were inef-
ficient to complete conversions or required extremely
prolonged reaction times.3,4 To our surprise, synthesis of
lipophilic secondary amines was completely selective (entry
9), which was presumably due to the produced hydrocarbons
residing on the cesium surface.
Next, our attention was directed toward N-alkylation of
amino acid derivatives due to demand in numerous syntheses
(Table 5).11 N-Alkylation of â-amino ether 13 gave rise to
the mixture of secondary and tertiary amines in 84% and
Primary and secondary bromides were generally applicable
to this methodology. As predicted, tertiary bromides were
resistant to alkylations under our conditions. One crucial
feature embedded in this protocol is the excellent chemo-
selectivity, where most added bromides delivered only the
Table 5. Chemoselective N-Alkylation of Amino Acid
Derivatives in the Presence of CsOH‚H2O
(8) Rationale for reversal of normally observed alkylation rates is
proposed to orginate from the amine-cesium ion complexes. Amine protons
in complex i should be sufficiently acidic to be abstracted by bases. On the
other hand, owing to the increased sterics in quatenary salt ii compared to
i, access of bases to available protons would be minimized, inhibiting the
alkylation of secondary amines.
(a) Constable, E. C. In Metals and Ligand ReactiVity; VCH Publishers:
New York, 1996; p 102. (b) Dehmlow, E. V.; Thieser, R.; Zahalka, H. A.;
Sasson, Y. Tetrahedron Lett. 1985, 26, 297. (c) Santhanalakshmi, J.; Raja,
T. Bull. Chem. Soc. Jpn. 1997, 70, 2829. (d) Ando, T.; Yamawaki, J. Chem.
Lett. 1979, 45. (e) Onaka, M.; Ishikawa, K.; Izumi, Y. Chem. Lett. 1982,
1783. (f) Blum, Z. Acta Chem. Scand. 1989, 43, 248. (g) Soong, L.-L.;
Leroi, G. E.; Popov, A. I. J. Solut. Chem. 1989, 18, 561.
Org. Lett., Vol. 1, No. 12, 1999
1895

15%, respectively, presumably mimicking the aforemen-
tioned unhindered amines. However, when amino alcohols12
encompassing valinol and leucinol were reacted with active
or unreactive bromides (entries 2 and 3), chemoselectivities
were excellent and the secondary amines were obtained in
satisfactory yields. As discussed above, only a catalytic
amount of cesium hydroxide was necessary with the employ-
ment of benzyl bromide to afford the dialkylamine in good
yield. Remarkablly, no O-alkylation was observed, and as a
result, the hydroxyl group was left intact.
Amino esters such as valine ester 15 were also smoothly
converted to the corresponding monoalkylated products with
various bromides (entries 4-6). To investigate possible side
pathways, reactions were performed intentionally under
relatively harsh conditions, for longer duration (entry 5) and
excess cesium hydroxide (entry 6). Racemizations were not
detected in alkylations of chiral substrates,13 and complica-
tions stemming from hydrolysis and subsequent esterification
were not experienced to a detectable extent. Thus, our
developed protocols are mild, efficient, and chemoselective,
averting common side reactions under basic conditions.
Another noteworthy feature is the ability to carry out this
C-N bond formation without the use of protecting groups
as demonstrated in entries 3-6, allowing for efficient
peptidomimetic syntheses.
In summary, cesium hydroxide promoted N-alkylation of
primary amines gives rise to the predominant or exclusive
synthesis of secondary amines, which are otherwise difficult
to prepare. This account illustrates a powerful potential since
the selective alkylation of various amines and amino acid
derivatives is carried out in a single step without the use of
unnecessary protecting groups. Furthermore, the reaction
conditions are mild and general, and the chemoselectivities
are greatly enhanced over the existing methods. Procedures
are also simple, convenient, and inexpensive, offering
alternatives in both laboratory- and industrial-scale prepara-
tions.14 It is strongly believed that this technology will be
of great significance as a solution to the existing problems
in numerous N-alkylations, providing a general synthetic
methodology. Further studies into the mechanism8 and
applications of these techniques will be reported in due
course.
Acknowledgment. Financial support from the USF
Research Council is gratefully acknowledged, as is support
from the H. Lee Moffitt Cancer Center & Research Institute.
The authors thank Ms. Feixia Chu for initial efforts on this
project. K.W.J. also acknowledges support and helpful
discussion from colleagues including the late Professor
Raymond N. Castle, to whom this paper is dedicated.
(9) Side reactions including elimination were not observed within our
detection limits.
OL9910417
(10) Bromination of the corresponding dibenzylamino alcohols was
developed in our laboratories, which will be published elsewhere. We found
that DMF catalyzed bromination using thionyl bromide in cyclohexane,
and the desired product was easily isolated on an even larger scale by either
precipitation as the hydrobromide salt or separation of the DMF layer
containing only the desired bromide.
(11) (a) Gray, B. D.; Jeffs, P. W. J. Chem. Soc., Chem. Commun. 1987,
1329. (b) Bhatt, U.; Mohamed, N.; Just, G. Tetrahedron Lett. 1997, 38,
3679. (c) Maurer, P. J.; Takahata, H.; Rapoport, H. J. Am. Chem. Soc. 1984,
106, 1095. (d) Bowman, W. R.; Coghlan, D. R. Tetrahedron 1997, 53,
15787.
(12) (a) Andre´s, J. M.; Barrio, R.; Mart´ınez, M. A.; Pedrosa, R.; Pe´rez-
Encabo, A. J. Org. Chem. 1996, 61, 4210. (b) Reetz, M. T.; Drewes, M.
W.; Schmitz, A. Angew. Chem., Int. Ed. Engl. 1987, 26, 1141.
(13) Optical rotations of the synthetic samples were matched with the
known values; see ref 11d. Observed values for pentenyl and benzyl
derivatives were -49.5° and -10.0°, respectively, whereas the reported
values were -50.2° and -9.9° for the same compounds.
(14) Representative Experimental Procedure: To activated powdered
4 Å molecular sieves (500 mg) in anhydrous N,N-dimethylformamide (8.3
mL), was added cesium hydroxide monohydrate (280 mg, 1.7 mmol), and
then the white suspension was vigorously stirred for 10 min. After
phenethylamine 3 (0.21 mL, 1.7 mmol) was added and followed by
additional 30 min of stirring, 1-bromobutane (0.21 mL, 2.0 mmol) was added
into the white suspension. The reaction was stirred for 20 h, filtered to
remove the molecular sieves and undissolved inorganic salts, and rinsed
several times with EtOAc. After the filtrate was concentrated to a nominal
volume by blowing air, the residue was taken up in 1 N NaOH, and extracted
with EtOAc (4 × 20 mL). The combined organic layers were washed with
brine, dried over anhydrous sodium sulfate, filtered, and concentrated in
Vacuo. Flash column chromatography (EtOAc-EtOH, 9:1 v/v) afforded
the secondary amine 4 (260 mg, 1.5 mmol; 89%) as a colorless oil as well
as tertiary amine 5 (40 mg, 0.17 mmol; 10%) as a pale yellow oil.
1896
Org. Lett., Vol. 1, No. 12, 1999