A one-pot preparation of 1,3-disubstituted azetidines

Article abstract of DOI:10.1021/jo061147x

(Chemical Equation Presented) A straightforward synthesis of 1,3-disubstituted azetidines has been accomplished via the alkylation of a primary amine with the bis-triflate of a 2-substituted-1,3-propanediol species. This transformation is carried out in o

Full text of DOI:10.1021/jo061147x

block the elimination pathway.6 Alternatively, 3-hydroxyaze-
tidines have been prepared from an amine and epichlorohydrin,
and the alcohol functionality can serve as a handle for further
elaboration.7 Despite the usefulness of these methods, no general
one-pot method exists for the preparation of 1,3-disubstituted
azetidines starting from 2-substituted-1,3-propanediols.
A One-Pot Preparation of 1,3-Disubstituted
Azetidines
Michael C. Hillier*,† and Cheng-yi Chen
Department of Process Research, Merck & Co., P.O. Box 2000,
Rahway, New Jersey 07065
SCHEME 1. Azetidine Formation via Bis-Tosylate
Displacement: Methyl versus tert-Butyl
michael_hillier@merck.com
ReceiVed June 5, 2006
A straightforward synthesis of 1,3-disubstituted azetidines
has been accomplished via the alkylation of a primary amine
with the bis-triflate of a 2-substituted-1,3-propanediol species.
This transformation is carried out in one reaction vessel, and
elimination of the alkylating reagent is generally not a major
byproduct. The scope of this methodology has been inves-
tigated using a variety 2-substituted-1,3-propanediols and
amine nucleophiles.
SCHEME 2. Azetidine Formation via Bis-Triflate
Activation
Substituted azetidines are unique heterocycles that can be
found in a number of biologically relevant compounds.1 Many
synthetic methods have been developed for the preparation of
these moieties, often involving the alkylation of an amine with
an activated three-carbon unit.2 For example, unsubstituted
N-alkyl azetidines can be assembled via intramolecular cycliza-
tion of activated amino propanols or by the double alkylation
of a primary amine using 1,3-diactivated propane reagents.3
3-Substituted azetidines can be obtained in similar fashion from
2-substituted-1,3-propanediol derivatives and amine nucleo-
philes.4 However, in some of these examples, elimination of
the alkylating reagent has been observed as a major reaction
byproduct.4c,5 One solution to this problem has been to use a
2,2-disubstituted-1,3-propanediol starting material in order to
As part of our own program of research,8 we became
interested in the synthesis of 3-(1-phenylethyl)azetidines 3 from
the corresponding diols 1 via the intermediate bis-tosylates 2
(Scheme 1). After screening a variety of bases and solvents,
the activated species 2a (1.5 equiv) was found to react slowly
with aminodiphenylmethane (1 equiv) in the presence of
NaHCO3 (3 equiv) in DMPU at 80 °C to give 3a (R ) Me) in
70% yield after 24 h. When the same conditions were applied
to the more sterically hindered substrate 2b, the desired azetidine
product 3b (R ) tBu) was formed in only 20% yield, even after
heating at 80 °C in a sealed vessel.9 We postulate that the greater
steric bulk of the starting material 2b inhibits alkylation of the
amine and subsequent cyclization. In light of this result, other
approaches to the azetidine 3b were examined, and a one-pot
method developed by Miller and co-workers6 using trifluo-
romethanesulfonic anhydride (Tf2O) as the activator (Scheme
2) was identified. Following this procedure, the diol 1b (1.05
equiv) was treated with Tf2O (2.2 equiv) in the presence of
† Current address: Abbott Laboratories, North Chicago, IL 60064.
(1) (a) Frigola, J.; Pare´s, J.; Corbera, J.; Van˜o´ Merce`, R.; Torrens, A.;
Ma´s, J.; Valent´ı, E. J. Med. Chem. 1993, 36, 801. (b) Pinder, A. R. Nat.
Prod. Rep. 1992, 9, 491.
(2) (a) Cromwell, N. H.; Phillips, B. Chem. ReV. 1979, 79, 331. (b) De
Kimpe, N. In ComprehensiVe Heterocyclic Chemistry II; Padwa, A., Ed.;
Pergamon: Tarrytown, New York, 1996; pp 507.
(3) (a) Szmuszkovicz, J.; Kane, M. P.; Laurian, L. G.; Chidester, C. G.;
Scahill, T. A. J. Org. Chem. 1981, 46, 3562. (b) Sammes, P. G.; Smith, S.
J. Chem. Soc., Perkin Trans. 1 1984, 2415. (c) Singh, P.; Jain, A. Ind. J.
Chem. 1988, 27B, 790. (d) Huszthy, P.; Bradshaw, J. S.; Krakowiak, K. F.;
Wang, T.; Dalley, N. K. J. Heterocycl. Chem. 1993, 30, 1197. (e) Zhao,
D.; Chen, C.; Xu, F.; Tan, L.; Tillyer, R.; Pierce, M. E.; Moore, J. R. In
Organic Reactions; Hart, D. J., Ed.; John Wiley & Sons: New York, 2000;
pp 12-21. (f) Haight, A. R.; Lallaman, J. E.; Wayne, G. S. U.S. Patent 6
124 474, 2000.
(4) (a) Gaj, B. J.; Moore, D. R. Tetrahedron Lett. 1967, 23, 2155. (b)
Higgins, R. H.; Eaton, Q. L.; Worth, L.; Peterson, M. V. J. Heterocycl.
Chem. 1987, 24, 255. (c) Juaristi, E.; Madrigal, D. Tetrahedron 1989, 45,
629. (d) Chong, J. M.; Sokoll, K. K. Synth. Commun. 1995, 25, 603.
(5) (a) Anderson, A. G.; Lok, R. J. J. Org. Chem. 1972, 37, 3953. (b)
Cromwell, N. H.; Soriano, D. S.; Doomes, E. J. Org. Chem. 1980, 45, 4983.
(c) Nozoe, T.; Shindo, K.; Wakabayashi, H.; Kurihara, T.; Ishikawa, S.
Collect. Czech. Chem. Commun. 1991, 56, 991. (d) Saulnier, M. G.;
Zimmermann, K.; Struzynski, C. P.; Sang, X.; Velaparthi, U.; Wittman,
M.; Frennesson, D. B. Tetrahedron Lett. 2004, 45, 397.
(6) Miller, R. A.; Lang, F.; Marcune, B.; Zewge, D.; Song, Z. J.; Karady,
S. Synth. Commun. 2003, 33, 3347.
(7) (a) Carruthers, N. I.; Wong, S.; Chan, T. J. Chem. Res., Synop. 1996,
430. (b) Billotte, S. Synlett 1998, 379. (c) Vuilhorgne, M.; Commerc¸on,
A.; Mignani, S. Chem. Lett. 1999, 605. (d) Dejaegher, Y.; Kuz´menok, N.
M.; Zvonok, A. M.; DeKimpe, N. Chem. ReV. 2002, 102, 29.
10.1021/jo061147x CCC: $33.50 © 2006 American Chemical Society
Published on Web 09/07/2006
J. Org. Chem. 2006, 71, 7885-7887
7885

TABLE 1. Generality of the Azetidine Formation
TABLE 2. Azetidine Formation with Complex Substrates
of the starting diol 5 (R1 ) tBu, entry 5) did not impact
conversion to product, and elimination was not observed as a
major byproduct even with the more acidic 2-phenyl-1,3-
propanediol (R1 ) Ph, entry 3). The nature of the amine
nucleophile was found to have a significant impact on the
outcome of this transformation. For example, when the HCl
salt of aminodiphenylmethane was employed, the azetidine
product 6e was produced in 39% yield (entry 6) compared to
86% yield obtained with the free base (entry 5). On the other
hand, the tosylate salt worked well, and the azetidine 6e was
formed in 84% yield. Aniline, a generally less nucleophilic
amine, reacted with the bis-triflate of 2-phenyl-1,3-propanediol,
but the product 6f was obtained in low yield (32%, entry 8).
Benzyl carbamate (entry 10) did not react under these conditions,
resulting in decomposition of the activated 1,3-diol. On the other
hand, tert-butylamine did react with the bis-triflate species, but
the desired azetidine product did not form and multiple
unidentified byproducts were obtained (entry 11).
Other conditions were briefly screened in an attempt to
improve the efficiency of the azetidine formation via the bis-
triflate. When excess amine nucleophile was employed, a 5%
higher yield of product was achieved, but this led to difficulties
during purification.13 Other bases were also examined with
varying degrees of success. For example, the use of Na2CO3
led to the formation of product, but in 10-15% lower yield
due to incomplete triflate formation.14 Reactive bases, such as
pyridine or N-methylimidazole, resulted in consumption of the
activated diol, but no desired azetidine products were formed.
Heavily functionalized 2-substituted-1,3-propanediols were
found to participate in this condensation reaction (Table 2). For
example, the 2-(1-phenylethyl)-1,3-propanediol substrates 1a
and 7a underwent triflate formation and reaction with amino-
diphenylmethane to give the corresponding products 3a and 8a
in 85 and 92% yield, respectively. The use of a chiral amine,
(S)-R-methylbenzylamine (98% ee), and the chiral diol 7b (94%
ee) gave product 8b, which could be isolated as a single
diisopropylethylamine (DIEA, 2.6 equiv) at -20 °C in aceto-
nitrile (ACN) and aged for 10-30 min.10 The intermediate bis-
triflate 4 was not isolated but was treated with excess DIEA
(2.6 equiv) and the amine nucleophile (1.0 equiv), followed by
heating to 70 °C. After 1 h at this temperature, the azetidine 3b
was obtained in 95% yield with no elimination byproducts being
detected.11 Clearly, use of the bis-triflate species 4 greatly
increases the rate of amine alkylation and azetidine formation
compared to that obtained with the bis-tosylate 2b. Another
advantage of this method is that the alkylating reagent 4 is
formed and utilized in one vessel, thereby obviating the need
to prepare this intermediate in a separate step. Encouraged by
the dramatic improvement observed using these conditions, the
scope of this reaction was examined with other substrates.
The condensation of commercially available 2-substituted-
1,3-propanediols 5 and various amines was carried out according
to the procedure outlined above (Table 1). In a number of cases,
the azetidine products 6 were obtained in good to excellent yield
(64-92%) using a slight excess of the diol.12 The steric bulk
(8) Baker, R. K.; Bao, J.; Miao, S.; Rupprecht, K. M. WO 2005/000809
A1, 2005.
(9) The remainder of the reaction mass balance was unreacted bis-tosylate
2b, mono-tosylate, and N-tosyl aminodiphenylmethane.
(10) Formation of the bis-triflate could be monitored by thin-layer
chromatography or by HPLC.
(11) No byproducts due to elimination of the bis-triflate were observed
by H NMR.
(13) On large scale, the removal of excess amine nucleophile is difficult
using nonchromatographic methods.
1
(12) The reaction yield is based on the amine as the limiting reagent.
(14) Observed by HPLC analysis of the reaction mixture.
7886 J. Org. Chem., Vol. 71, No. 20, 2006

SCHEME 3. Azetidine Formation with Polyols
1,3-propanediols. This method has broad substrate scope, works
well with a variety of functionalized chiral or achiral diol
substrates, and does not require preparation of the alkylating
species as a separate step. In general, sterically bulky diols react
smoothly under these conditions, and elimination of the alky-
lating reagent is not a major reaction pathway. On the other
hand, sterically hindered and electron-poor amines are not good
coupling partners, but chiral amines work well with no race-
mization.
Experimental Section
diastereomer in 90% yield after purification. The reaction of
(S)-phenylalanine methyl ester (99% ee) with the bis-triflate of
2-phenyl-1,3-propanediol 7c gave product 8c in good yield
(73%) and with no detectable racemization.15
General Azetidine Formation Procedure. To a solution of the
diol (5 mmol) in dry ACN (10 mL) at -20 °C was slowly added
trifluoromethanesulfonic anhydride (10.5 mmol) over 10-20 min
followed by diisopropylethylamine (DIEA, 12.5 mmol) over 10-
20 min. Both reagents were added at such a rate as to maintain the
internal reaction temperature below -10 °C, and the resulting
reaction mixture was aged for 10-30 min at -20 to -10 °C.
Additional DIEA (12.5 mmol) was then added over 5 min followed
by the amine (4.75 mmol) over 5 min, and the reaction was heated
to 70 °C for 1-2 h. Solvent was removed in vacuo, and the resulting
crude reaction mixture was purified via silica gel chromatography
to give the azetidine products in the yields indicated.
Polyol substrates were found to undergo activation and
subsequent reaction with varying results (Scheme 3). For
example, the triol 9 was converted to the triflate followed by
reaction with aminodiphenylmethane to give the dimeric product
10 in 32% yield. Apparently, with this substrate, triflate
displacement and elimination is favored over cyclization to give
azetidine products. The reaction of pentaerythritol 11 gave the
spirocyclic azetidine dimer 12 in 35% yield when excess Tf2O
(4.2 equiv), DIEA (10 equiv), and the amine (3.8 equiv) were
employed.16
Acknowledgment. The authors thank Dr. Ross A. Miller
for useful discussions.
In conclusion, we have demonstrated the one-pot formation
of 1,3-disubstituted azetidines via the reaction of amine nu-
cleophiles with in situ prepared bis-triflates of 2-substituted-
Supporting Information Available: Experimental details for
the synthesis of 2-substituted-1,3-propanediols 1a,b and 7a,b and
the bis-tosylates 2a,b, full characterization data for all compounds,
and 1H NMR and 13C NMR spectra. This material is available free
of charge via the Internet at http://pubs.acs.org.
(15) As determined by comparison to a racemic standard according to
chiral SFC analysis.
(16) A number of other unidentified products were obtained in this
reaction.
JO061147X
J. Org. Chem, Vol. 71, No. 20, 2006 7887