A Tandem Three-Phase Reaction for Preparing Secondary Amines with Minimal Side Products

Article abstract of DOI:10.1021/ol0269401

(Matrix Presented) A new method for the preparation of secondary amines has been reported. Complementary solution-phase and solid-phase synthesis highlight the process. Amines are obtained in good yields free from the usual byproducts of reductive aminati

Full text of DOI:10.1021/ol0269401

ORGANIC
LETTERS
2002
Vol. 4, No. 26
4611-4613
A Tandem Three-Phase Reaction for
Preparing Secondary Amines with
Minimal Side Products
Jeffrey C. Pelletier,* Ambar Khan, and Zhilian Tang
DiVision of Chemical Sciences, Wyeth Research, Pearl RiVer, New York 10965
Pelletj@wyeth.com
Received September 20, 2002
ABSTRACT
A new method for the preparation of secondary amines has been reported. Complementary solution-phase and solid-phase synthesis highlight
the process. Amines are obtained in good yields free from the usual byproducts of reductive amination. Secondary amines are unreactive, so
overalkylation does not occur. The procedure can be used interchangeably for traditional or parallel synthesis settings.
The genesis of combinatorial chemistry is linked to the
discovery of solid-phase peptide synthesis1 and its modifica-
tion to more elaborate solid-phase organic synthesis.2 This
eventually led to resin-bound reagents and scavengers as aids
for solution-phase synthetic processes. Both solid-phase
synthesis and solution-phase synthesis with resin-bound
scavengers/reagents are performed in two-phase systems
where filtration is used to isolate products and spent reagents/
byproducts, respectively.3 These approaches to the prepara-
tion of discrete compounds (individual and parallel) are now
commonplace in many labs.
Reports of synthetic methods involving more than two
phases are less common. Early accounts of three-phase
reaction mixtures dealt with mechanistic studies where
reactive intermediates were released into solution from a
resin-bound starting material and subsequently trapped by a
substrate bound to a second resin.4 The technique of three
(or more) phases working in tandem to provide a resin bound
product from a resin-bound starting material, or “resin to
resin transfer” (RRTR), requires a transfer agent or chaperone
to mobilize resin-bound starting material and hence catalyze
the reaction5 (Figure 1). Normally, soluble substrates A and
B could react under little control to provide desired as well
as undesired products. Polymer-bound substrates, however,
are physically separated from each other even though they
are within the same reaction vessel; therefore, little if any
interaction occurs between them. This is sometimes referred
to as the “Wolf and Lamb” effect.6
Solution-phase preparations of target compounds with two
or more reagent resins present in a single flask have also
been reported. Deuterium labeling of primary alcohols via
oxidation-reduction7 and a 2-aminothiazole synthesis8 have
used reagents bound to inorganic resins, while the preparation
of alkoxypyrrazoles has been achieved using three resin-
bound reagents in a single-pot operation.9 Also notable are
the “fluorous” methods in which aqueous, organic, and highly
(4) (a) Rebek, J.; Gavina, F. J. Am. Chem. Soc. 1974, 96, 7112-7114.
(b) Rebek, J., Jr. Tetrahedron 1979, 35, 723-731. (c) Gavina, F.; Costero,
A. M.; Andreu, M. R.; Carda, M.; Luis, S. V. J. Am. Chem. Soc. 1988,
110, 4017-4018. (d) Gavina, F.; Costero, A. M.; Andreu, M. R.; Luis, S.
J. Org. Chem. 1988, 53, 6112-6113.
(1) Merrifield, R. B. J. Am. Chem. Soc. 1963, 85, 2149-2154.
(2) Reviews: (a) Wendeborn, S.; De Mesmaker, A.; Brill, W. K.-D.;
Berteina, S. Acc. Chem. Res. 2000, 33, 215-224. (b) Watson, C. Angew.
Chem., Int. Ed. 1999, 38, 1903-1908. (c) Booth, S.; Hermkens, P. H. H.;
Ottenheijm, H. C. J.; Rees, D. C. Tetrahedron 1998, 54, 15385-15443.
(3) (a) Kaldor, S. W.; Siegel, M. G.; Frits, J. E.; Dressman, B. A.; Hahn,
P. J. Tetrahedron Lett. 1996, 37, 7193-7196. (b) Flynn, D. L.; Crich, J.
Z.; Devraj, R. V.; Hockerman, S. L.; Parlow, J. J.; South, M. S.; Woodard,
S. J. Am. Chem. Soc. 1997, 119, 4874-4881. (c) Booth, J. R.; Hodges, J.
C. J. Am. Chem. Soc. 1997, 119, 4882-4886.
(5) (a) Hamuro, Y.; Scialdone, M. A.; DeGrado, W. F. J. Am. Chem.
Soc. 1999, 121, 1636-1644. (b) Gravel, M.; Berube, B. D.; Hall, D. G. J.
Comb. Chem. 2000, 2, 228-231. (c) Gravel, M.; Thompson, K. A.; Zak,
M.; Berube, C.; Hall, D. G. J. Org. Chem. 2002, 67, 3-15.
(6) Cohen, B. J.; Kraus, M. A.; Patchornik, A. J. Am. Chem. Soc. 1981,
103, 7620-7629.
(7) Kim, B.; Regen, S. L. Tetrahedron Lett. 1983, 24, 689-690.
(8) Kodomari, M.; Aoyama, T.; Suzuki, Y. Tetrahedron Lett. 2002, 43,
1717-1720.
(9) Parlow, J. J. Tetrahedron Lett. 1995, 36, 1395-1396.
10.1021/ol0269401 CCC: $22.00 © 2002 American Chemical Society
Published on Web 12/03/2002

Scheme 1. Tandem Three-Phase Preparation of a Secondary
Amine
Figure 1. Resin to resin transfer reaction.
fluorinated solvents are used in a three-phase solvent system
for compound purification.10
We report here a multiphase reaction that combines solid-
phase and solution-phase methodologies to produce second-
ary amines that are free of the usual side products (carbonyl
starting materials, alcohols from reduction of the carbonyl
group, and products from overalkylation). A resin-bound
aldehyde (in the imine form) can undergo a transimination/
cleavage equilibrium with a solution-phase primary amine
to produce a solution-phase imine. This imine in turn serves
as a substrate for a resin bound reducing agent leaving the
secondary amine product in solution.11
A graphic example is shown in Scheme 1. 3-Fluorobenz-
aldehyde was reacted with aminomethyl resin (AM resin)
under known conditions12 to provide the resin bound imine
(1). This resin was treated with n-butylamine (2, 0.5 equiv)
and resin-bound borohydride (5, 2 equiv).13 After 14 h of
shaking, the resins were separated by filtration and the filtrate
was treated with concentrated HCl and then evaporated.14
Analysis of the product mixture indicated N-(3-fluorobenzyl)-
butylamine (6) as the sole compound present in 78% yield
(Figure 2a). A similar reaction was run under typical solution-
phase conditions (1.0 equiv of butylamine and 3-fluorobenz-
aldehyde and 1.3 equiv of sodium triacetoxyborohydride in
dichloromethane at room temperature). The product mixture
yielded the desired secondary amine (expected product)
heavily contaminated with the tertiary amine (overalkylated
product) and starting aldehyde (Figure 2b).
The process, which takes place in a single reaction vessel,
can be considered a tandem three-phase reaction. The original
starting materials on resin (phase 1) and in solution (phase
(10) (a) Luo, Z.; Zhang, Q.; Oderaotoshi, Y.; Curran, D. P. Science 2001,
291, 1766-1769. (b) Curran, D. P. Angew. Chem., Int. Ed. 1998, 37, 1175-
1196. (c) Studer, A.; Hadida, S.; Ferritto, R.; Kim, S.-Y.; Jeger, P.; Wipf,
P.; Curran, D. P. Science 1997, 275, 823-826.
(11) A similar example has recently been reported; see: Hemming, K.;
Bevan, M. J.; Loukou, C.; Patel, S. D.; Renaudeau, D. Synlett 2000, 1565-
1568.
(12) (a) Look, G. C.; Murphy, M. M.; Campbell, D. A.; Gallop, M. A
Tetrahedron Lett. 1995, 36, 2937-2940. (b) Szardenings, A. K.; Burkoth,
T. S.; Look, G. C.; Campbell, D. A J. Org. Chem. 1996, 61, 6720-6723.
(13) Aminomethylpolystyrene resin (2% DVB, 200-400 mesh, 1.13
mmol/g loading) purchased from Novabiochem (product no. 01-64-0100).
Resin-bound borohydride (Amberlite IRA 400, 2.5 mmol/g loading) was
purchased from Aldrich Chemical Co. (product no. 32,864-2).
(14) Treatment with a small excess of concentrated HCl ensured
hydrochloride formation of products as well as any starting amine that
remained, thus preventing evaporation and allowing for accurate product
analysis.
Figure 2. HPLC trace comparison of product mixtures from the
tandem three-phase preparation of 6 (Figure 2a) and a typical
solution-phase preparation of 6 (Figure 2b, see text for a description
of experiment). Peak A: butyl-(3-fluorobenzyl)amine. Peak B:
mixture of 3-fluorobenzaldehyde and bis(3-fluorobenzyl)butylamine.
4612
Org. Lett., Vol. 4, No. 26, 2002

2) react to form an intermediate in solution that is trans-
formed by a reagent resin (phase 3) to form a soluble product.
Ideally, filtration and evaporation are all that is needed for
product isolation. Imine resin (phase 1) and borohydride resin
(phase 3) are physically separate and therefore do not react.
Typical side products such as alcohol (aldehyde reduction
product), overalkylated amine, and starting aldehyde were
not detected. Under these conditions the amount of secondary
amine in the reaction mixture determines how much aldehyde
reacts. Throughout the progress of the reaction, the excess
aldehyde remained in a “prescavenged” state, so no steps
were necessary to remove the excess after completion of the
reaction.
Scheme 2. Preparation of â-3 Agonists from the Tandem
Three-Phase Reaction for Secondary Amines
An in-house program designed to discover novel, selective
â-3 agonists required the preparation of secondary amines
(12a-c) to fulfill structure-activity relationship (SAR)
requirements. The â-3 adrenergic receptor is selectively
located on the surface of adipose cells and serves to regulate
lipid metabolism upon stimulation with the endogenous
ligand.15 A selective agonist of the receptor may find
indication in obesity treatment. The method described herein
appeared to be suitable for their preparation. Furthermore,
it could potentially be used to produce focused libraries of
similar analogues. As outlined in Scheme 2, 4-(2-hydroxym-
ethyl)piperidine (7) was treated with excess 4-ethylbenze-
nesulfonyl chloride (8) as well as polymer-supported scav-
engers3 to give the product sulfonamide (9) in 93% yield.
The alcohol was selectively oxidized to the corresponding
aldehyde with chromic acid on resin16 (8 equiv). Although
no overoxidation to the acid took place, the product mixture
was always accompanied by approximately 20% starting
alcohol (9). More oxidizing agent, longer reaction times, and
different solvents led to inferior results. Aldehyde purification
suitable for library work occurred when the mixture was
treated with aminomethyl resin under the normal conditions
for scavenging electrophiles.3 The phase switch allowed the
alcohol contaminant to be washed away, and conveniently
provided the resin-bound imine (10) required for the next
step. Hence, resin 10 was treated with primary amines
(11a-c, 0.80 equiv)17 under the conditions described above
for secondary amine formation. Two of the products were
isolated in good yields (12a and 12c), while the yield for
the remaining product (12b) was lower due to the insolubility
of the starting amine, which was recovered from the product
mixture. As in the case above, byproducts were not detected.
material, cleavage) and solution-phase (resin-bound boro-
hydride reduction) methodology in a single vessel. The
procedure uses readily available reagents, provides pure
products, and can be run in parallel format. In addition, this
technique has been successfully applied to the generation of
proprietary secondary amine libraries, and the results will
be reported in due course.
Acknowledgment. We thank Wyeth Research for a
summer internship to A.K., John Ellingboe for support and
helpful discussions, and Larry Mallis for analytical chemistry
expertise.
In conclusion, a new tandem three-phase method for the
preparation of secondary amines has been described that
involves a mixture of solid-phase (resin-bound starting
Supporting Information Available: Experimental details
and characterization data for compounds 12a-c. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(15) Kordik, C. P.; Reitz, A. B. J. Med. Chem. 1999, 42, 181-201.
(16) Cainelli, G.; Cardillo, G.; Orena, M.; Sandri, S. J. Am. Chem. Soc.
1976, 98, 6737-6738.
(17) (a) For the preparation of 11b; see: Bell, M. G.; Crowell, T. A.;
Matthews, D. P.; McDonald, J. H.; Neel, D. A.; Shuker, A. J.; Winter, M.
A. U.S. Patent 5786356, 1998. (b) For the preparation of 11c; see: Hu, B.;
Sum, F.-W. WO 0206221, 2002.
OL0269401
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