N,N′-carbonyldiimidazole-mediated cyclization of amino alcohols to substituted azetidines and other N-heterocycles

Article abstract of DOI:10.1021/jo060130b

Amino alcohols are important synthons for N-heterocycles. We have developed an efficient method to activate hydroxyl groups, which avoids the use of toxic reagents and tolerates a wide variety of functional groups. Our strategy has been applied to the syn

Full text of DOI:10.1021/jo060130b

N,N′-Carbonyldiimidazole-Mediated Cyclization of Amino Alcohols
to Substituted Azetidines and Other N-Heterocycles
Renata Marcia de Figueiredo,† Roland Fro¨hlich,‡ and Mathias Christmann*,†
Institut fu¨r Organische Chemie der RWTH Aachen, Landoltweg 1, 52074 Aachen, Germany, and
Organisch-Chemisches Institut der UniVersita¨t Mu¨nster, Corrensstrasse 40, 48149 Mu¨nster, Germany
christmann@oc.rwth-aachen.de
ReceiVed January 20, 2006
Amino alcohols are important synthons for N-heterocycles. We have developed an efficient method to
activate hydroxyl groups, which avoids the use of toxic reagents and tolerates a wide variety of functional
groups. Our strategy has been applied to the synthesis of functionalized p-methoxyphenyl-protected
azetidines, pyrrolidines, and piperidines. The required amino alcohols were synthesized according to an
optimized proline-catalyzed Mannich protocol. An azetidine analogue of ezetimibe was synthesized to
demonstrate the potential for the synthesis of drug-like molecules.
Introduction
Saturated N-heterocycles1 represent an important class of
compounds that exhibit biological activity. Despite the develop-
ment of many useful strategies for their synthesis, the intramo-
lecular displacement of a hydroxyl group with an amino group
remains the most predictable. Coupled together with the
Mannich reaction,2 many natural and non-natural bioactive
compounds could be accessed in an efficient manner, as
illustrated in Figure 1.3
FIGURE 1. Mannich-Cyclization approach to N-heterocycles.
To induce the cyclization of a given amino alcohol, the
hydroxyl group requires activation (Scheme 1). Insensitive
substrates can be activated with the aid of strong mineral acids,
such as hydrobromic acid, leading to cyclic amines as their
hydrobromide salts (eq 1). Often, however, these harsh condi-
tions are incompatible with functional groups. Therefore, milder
protocols have been developed that involve the activation of
the hydroxyl group, for example, as a mesylate (eq 2), followed
by base-induced ring closure.4 The most common methods today
SCHEME 1. Mass Balance of Cyclization Processes
† Institut fu¨r Organische Chemie der RWTH Aachen.
‡ Organisch-Chemisches Institut, Universita¨t Mu¨nster.
(1) Hutchinson, A.; Nadin, A. J. Chem. Soc., Perkin Trans. 1 2000, 2862.
(2) (a) Arend, M.; Westermann, B.; Risch, N. Angew. Chem., Int. Ed.
1998, 37, 1044. (b) Denmark, S. E.; Nicaise, O. J.-C. In ComprehensiVe
Asymmetric Catalysis; Jacobsen, E. N., Pfaltz, A., Yamamoto, H., Eds.;
Springer: Berlin, 1999; Vol. 2, Chapter 26.2. (c) Cordova, A. Acc. Chem.
Res. 2004, 37, 102.
(3) For another interesting approach, see: Banwell, M. G.; Beck, D. A.
S.; Smith, J. A. Org. Biomol. Chem. 2004, 2, 157.
(4) Pulz, R.; Al-Harrasi, A.; Reissig, H.-U. Org. Lett. 2002, 4, 2353.
involve Mitsunobu-type activation5 with DEAD (eq 3) or Appel-
type protocols using carbon tetrabromide and triphenylphos-
phine.6 The drawback of these protocols is the use of toxic and
10.1021/jo060130b CCC: $33.50 © 2006 American Chemical Society
Published on Web 04/22/2006
J. Org. Chem. 2006, 71, 4147-4154
4147

de Figueiredo et al.
SCHEME 2. Mannich Dimerization of Functionalized
expensive reagents. In addition, byproducts are formed that are
difficult to separate or to recycle. Our new method employs
readily available and nontoxic 1,1-carbonyldiimidazole (CDI)
and affords imidazole and carbon dioxide as the byproducts (eq
4).
Aldehydes
In a recent communication,7 we reported the synthesis of 1,2-
disubstituted N-heterocycles, comprised of a proline-catalyzed
Mannich reaction,8,9 followed by a cyclization with Staab’s
reagent10 (1,1-carbonyldiimidazole). In this paper, we want to
give a full account of our studies and extend the strategy to the
synthesis of higher substituted heterocycles. In addition, the
unexpected oxidative cleavage of diarylazetidines provides
access to chiral amino ketones.
SCHEME 3. Cyclization of γ-Amino Alcohols
Results and Discussion
As an organocatalytic11 entry into N-heterocyclic systems,
we were investigating the proline-catalyzed self-Mannich reac-
tion or Mannich dimerization of aldehydes,12 bearing an
additional site for functionalization. After a good deal of
experimentation, we found that the Mannich reaction with tert-
butyldimethylsiloxy-protected aldehydes13 1a and 1b gave the
desired products 2a and 2b in up to 98% ee (Scheme 2).
Acetonitrile as the solvent and a very low temperature (-40
°C) were the essentials for a high selectivity.
(5) (a) Mitsunobu, O. Synthesis 1981, 1. (b) Itoh, T.; Miyazaki, M.;
Nagata, K.; Yokoya, M.; Nakamura, S.; Oshawa, A. Heterocycles 2002,
58, 115.
(6) (a) Appel, R. Angew. Chem., Int. Ed. 1975, 14, 801. (b) Harris, J.
M.; Padwa, A. J. Org. Chem. 2003, 68, 4371. (c) Pu, X.; Ma, D. J. Org.
Chem. 2003, 68, 4400.
To determine the relative configuration of the major diaster-
eomer, we wanted to convert amino alcohol 2b into the cyclic
carbamate derivative 4. For N,N-dialkyl â-amino alcohols, the
CDI method usually affords the corresponding oxazinones in
high yields.14 However, when 2b and CDI were refluxed in
acetonitrile for 12 h, not even a trace of the desired 1,3-oxazin-
2-one 4 was detected. Instead, carbamate 3 had formed, which
refused to cyclize to 4. Disappointed by this result, in a final
attempt, crude 3 was heated to 150 °C in a Kugelrohr apparatus
under high vacuum. To our surprise, not the desired carbamate,15
but the azetidine 5b was formed (Scheme 3).
To test the scope and limitation of this azetidine synthesis,16,17
a series of amino alcohols derived from proline-catalyzed
Mannich reactions was subjected to our cyclization protocol.
Benzylic (Table 1, entries 3, 8-10) as well as aliphatic
p-methoxyphenyl (PMP) amines (Table 1, entries 1-2, 4-7)
were used in the reaction. In addition, standard protecting groups
such as acetates (entries 4 and 5), TBS ethers (entries 1-3),
and acetals (entries 9 and 10) were tested, which would allow
for further functionalization of the products (vide infra). The
method is not limited to the synthesis of 2,3-cis-azetidines (entry
5), though we mainly examined syn-amino alcohols as a result
of their preferential formation in the proline-catalyzed Mannich
process.18
(7) Mu¨nch, A.; Wendt, B.; Christmann, M. Synlett 2004, 2751.
(8) (a) List, B. J. Am. Chem. Soc. 2000, 122, 9336. (b) List, B.; Pojarliev,
P.; Biller, W. T.; Martin, H. J. J. Am. Chem. Soc. 2002, 124, 827. (c)
Co´rdova, A.; Notz, W.; Zhong, G.; Betancort, J. M.; Barbas, C. F., III. J.
Am. Chem. Soc. 2002, 124, 1842. (d) Co´rdova, A.; Watanabe, S.-i.; Tanaka,
F.; Notz, W.; Barbas, C. F., III. J. Am. Chem. Soc. 2002, 124, 1866. (e)
Watanabe, S.; Co´rdova, A.; Tanaka, F.; Barbas, C. F., III. Org. Lett. 2002,
4, 4519. (f) Co´rdova, A.; Barbas, C. F., III. Tetrahedron Lett. 2002, 43,
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C. F., III. J. Org. Chem. 2003, 68, 9624. (i) Hayashi, Y.; Tsuboi, W.; Shoji,
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Ed. 2003, 42, 3677. (k) Itoh, T.; Yokoya, M.; Miyauchi, K.; Nagata, K.;
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A. Angew. Chem., Int. Ed. 2004, 43, 6528. (m) Co´rdova, A. Chem.sEur.
J. 2004, 10, 1987. (n) Notz, W.; Watanabe, S.-i.; Chowdari, N. S.; Zhong,
G.; Betancort, J. M.; Tanaka, F.; Barbas, C. F., III. AdV. Synth. Catal. 2004,
346, 1131. (o) Funabiki, K.; Nagamori, M.; Goushi, S.; Matsui, M. Chem.
Commun. 2004, 1928. (p) Cobb, A. J. A.; Shaw, D. M.; Longbottom, D.
A.; Gold, J. B.; Ley, S. V. Org. Biomol. Chem. 2005, 3, 84. (q) Zhuang,
W.; Saaby, S.; Jørgensen, K. A. Angew. Chem., Int. Ed. 2004, 43, 4476. (r)
Westermann, B.; Neuhaus, C. Angew. Chem., Int. Ed. 2005, 44, 4077. (s)
Enders, D.; Grondal, C.; Vrettou, M.; Raabe, G. Angew. Chem., Int. Ed.
2005, 44, 4079. (t) Fustero, S.; Jime´nez, D.; Sanz-Cervera, J. F.; Sa´nchez-
Rosello´, M.; Esteban, E.; Simo´n-Fuentes, A. Org. Lett. 2005, 7, 3433. (u)
Ibrahem, I.; Co´rdova, A. Tetrahedron Lett. 2005, 46, 2839.
(9) For other leading references, see: (a) Wenzel, A. G.; Jacobsen, E.
N. J. Am. Chem. Soc. 2002, 124, 12964. (b) Trost, B. M.; Terrell, L. R. J.
Am. Chem. Soc. 2003, 125, 338. (c) Kobayashi, S.; Matsubara, R.;
Nakamura, Y.; Kitagawa, H.; Sugiura, M. J. Am. Chem. Soc. 2003, 125,
2507. (d) Matsunaga, S.; Kumagai, N.; Harada, S.; Shibasaki, M. J. Am.
Chem. Soc. 2003, 125, 4712. (e) Josephsohn, N. S.; Snapper, M. L.;
Hoveyda, A. H. J. Am. Chem. Soc. 2004, 126, 3734. (f) Uraguchi, D.;
Terada, M. J. Am. Chem. Soc. 2004, 126, 5356. (g) Akiyama, T.; Itoh, J.;
Yokota, K.; Fuchibe, K. Angew. Chem., Int. Ed. 2004, 43, 1566.
(10) (a) Staab, H. A. Angew. Chem., Int. Ed. 1962, 1, 351. (b) Staab, H.
A.; Bauer, H.; Schneider, K. M. Azolides in Organic Synthesis and
Biochemistry; Wiley-VCH: Weinheim, Germany, 2002.
All reactions were carried out in a Kugelrohr apparatus. The
imidazole formed in the reaction as well as azetidines of low
(13) Mann, S.; Carillon, S.; Breyne, O.; Marquet, A. Chem.sEur. J. 2002,
2, 439.
(14) (a) Tsuge, H.; Okano, T.; Eguchi, S. J. Chem. Soc., Perkin Trans.
1 1995, 2761. (b) Ella-Menye, J.-R.; Sharma, V.; Wang, G. J. Org. Chem.
2005, 70, 463.
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von Schnering, H. G. Angew. Chem., Int. Ed. 1994, 33, 1298.
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Chem. 2004, 1, 133.
(17) Barluenga, J.; Sanz, R.; Fananas, F. J. J. Org. Chem. 1997, 62, 5953.
(18) For a complimentary approach leading exclusively to the anti
products, see: Enders, D.; Gries, J.; Kim, Z.-S. Eur. J. Org. Chem. 2004,
4471.
(11) (a) Asymmetric Organocatalysis; Berkessel, A., Gro¨ger, H., Eds.;
Wiley-VCH: Weinheim, Germany, 2005. Reviews: (b) Seayad, J.; List,
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Chem., Int. Ed. 2004, 43, 5138.
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4148 J. Org. Chem., Vol. 71, No. 11, 2006

N,N′-Carbonyldiimidazole-Mediated Cyclization
TABLE 1. Synthesis of Azetidines
SCHEME 5. Synthesis of 2,4-Substituted Azetidines
amino
yield
(%)
entry alcohol azetidine
R2
R1
1
2
3
4
5a
6
7
8
9
2a
2b
2c
2d
2e
2f
2g
2h
2i
5a
5b
5c
5d
5e
5f
5g
5h
5i
(CH2)2OTBS
(CH2)3OTBS
(CH2)3OTBS
(CH2)2OAc
(CH2)2OAc
Me
(CH2)3OTBS
(CH2)4OTBS
Ph
(CH2)3OAc
(CH2)3OAc
Et
Pr
Ph
Ph
73
71
74
82
84
71
75
82
86
CDI-mediated cyclization. We submitted the known22 amino
alcohols 7a and 7b to our cyclization reaction with CDI (Scheme
5). The corresponding azetidines 8a and 8b were obtained in
good to excellent yields, whereas the amino alcohol 923 failed
to cyclize to the desired bicyclic system.
Et
Me
Interestingly, the above-mentioned cyclizations occur with
clean inversion of configuration at the C-O carbon atom (7a
f 8a, Scheme 6, eq 1). This clearly supports an SN2-type
mechanism, where the C-N bond formation and the decar-
boxylation occur simultaneously. Our results nicely complement
the findings of Mulvihill24 and Szmuszkovicz.25 They showed
that benzylic hydroxyl groups bearing a tertiary â-amino group
can be substituted under retention of configuration with imi-
dazole (11 f 14) using CDI. The observed stereochemical
outcome was explained with the intermediacy of an aziri-
dinium-imidazolyl ion pair 13 (eq 2). The question of why
the formation of the four-membered N-heterocycle is faster than
the ring closure to the cyclic carbamate cannot be answered at
this point. Recent competition experiments26 showed that the
cyclizations to the azetidine can under certain circumstances
even surpass the piperidine formation.
(CH2)3CH-
[O-(CH2)2-O]
(CH2)3CH-
[O-(CH2)2-O]
10
2j
5j
4-C6H4F
90
a The minor anti-diastereomer from the Mannich reaction was used to
obtain the corresponding azetidine with anti-configuration.
SCHEME 4. Functionalization of 5j
molecular weight condense in the receiving flask. The nonpolar
azetidines are easily separated by filtration through silica gel.
The relative stereochemistry in the azetidine ring can be easily
deduced from NOE experiments. For compound 5i, an X-ray
structure (see the Supporting Information) was obtained that
supports our structural assignment.
All azetidines were accessible in just two synthetic steps. To
demonstrate their facile conversion into drug-like molecules,
5j was treated with acid, which resulted in the liberation of the
carbonyl group. The addition of commercially available 4-fluo-
rophenylmagnesium bromide to the crude aldehyde afforded an
azetidine relative (6) of ezetimibe19 as a separable 1:1 mixture
of diastereomers (Scheme 4). Recently, Carreira et al. have
shown that azetidine analogues are as potent as their parent
â-lactams.20 Similar as in â-lactam drugs such as ezetimibe,
the central azetidine moiety can be regarded as a scaffold that
places the pharmacophoric groups in the correct orientation. We,
therefore, investigated the possibility of extending this meth-
odology to azetidines with other substitution patterns.
To apply our method to the synthesis of larger rings,27 the
primary alcohol 2a was protected as TBDPS ether, and the TBS
groups were subsequently removed with p-toluenesulfonic acid
in methanol (Scheme 7). When the resulting diol 15 was heated
with 3 equiv of CDI in acetonitrile, the cyclization occurred
smoothly. The remaining carbamate was cleaved with 2 N
NaOH/THF. Interestingly, the disubstituted pyrrolidine 16 was
observed almost exclusively.
Piperidine 17 was obtained in two steps from 2c, which was
synthesized in a three-component Mannich reaction of 5-tert-
butyldimethylsilyloxypentanal and benzaldehyde as a noneno-
lizable Mannich acceptor (Scheme 8). The TBS group was
cleaved (TBAF), and the resulting diol was refluxed with CDI
in acetonitrile for 2 h. After removal of the solvent, the reaction
mixture was heated to 150 °C under high vacuum in a Kugelrohr
apparatus to facilitate the decarboxylative cyclization. Hydrolysis
of the remaining carbamate afforded piperidine 17 in 60% yield.
The PMP group of 5g was removed easily by oxidation with
ceric ammonium nitrate (CAN).28 To facilitate the isolation, the
crude amine was treated with Boc2O to afford the Boc-protected
azetidine 18 in 72% yield for two steps (Scheme 9, eq 1).
However, when azetidine 5h was subjected to this deprotection
The synthesis of 2,4-disubstituted azetidines has been achieved
by displacement of 1,3-dibromides or -mesylates with a mono-
substituted amine.21 Formally, these heterocycles can also be
accessed by a proline-catalyzed addition of ketones to imines,
followed by reduction to the amino alcohols and subsequent
(22) Keck, G. E.; Truong, A. P. Org. Lett. 2002, 4, 3131.
(23) Wu, Y.-S.; Cai, J.; Hu, Z.-Y.; Lin, G.-X. Tetrahedron Lett. 2004,
45, 8949.
(24) Mulvihill, M. J.; Cesario, C.; Smith, V.; Beck, P.; Nigro, A. J. Org.
Chem. 2004, 69, 5124.
(25) Totleben, M. J.; Freeman, J. P.; Szmuszkovicz, J. J. Org. Chem.
1997, 62, 7319.
(26) Kise, N.; Hirano, Y.; Tanaka, Y. Org. Lett. 2006, 8 (7), 1323.
(27) (a) Buffat, M. G. P. Tetrahedron 2004, 60, 1701. (b) Weintraub, P.
M.; Sabol, J. S.; Kane, J. M.; Borcherding, D. R. Tetrahedron 2003, 59,
2953.
(19) (a) Clader, J. W. J. Med. Chem. 2004, 47, 1. (b) Earl, J.; Kirkpatrick,
P. Nat. ReV. Drug DiscoVery 2003, 2, 97.
(20) Kvarno, L.; Werder, M.; Hauser, H.; Carreira, E. M. J. Med. Chem.
2005, 48, 6035.
(21) For other approaches, see: (a) Kozikowski, A. P.; Tu¨ckmantel, W.;
Liao, Y.; Manev, H.; Ikonomovic, S.; Wroblewski, J. T. J. Med. Chem.
1993, 36, 2706. (b) Hoshino, J.; Hiraoka, J.; Hata, J.; Savada, S.; Yamamoto,
Y. J. Chem. Soc., Perkin Trans. 1 1995, 693. (c) Anzai, M.; Toda, A.;
Ohno, H.; Takemoto, Y.; Fujii, N.; Ibuka, T. Tetrahedron Lett. 1999, 40,
7393. (d) Marinetti, A.; Hubert, P.; Geneˆt, J.-P. Eur. J. Org. Chem. 2000,
1815. (e) Guanti, G.; Riva, R. Tetrahedron: Asymmetry 2001, 12, 605.
(28) Hughes, G.; Kimura, M.; Buchwald, S. L. J. Am. Chem. Soc. 2003,
125, 11253.
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de Figueiredo et al.
SCHEME 6. Mechanism of CDI-Mediated Cyclizations
SCHEME 7. Synthesis of Pyrrolidine 16
SCHEME 8. Synthesis of Piperidine 17
mmol). The mixture was stirred for 2 h at this temperature and
then kept in a freezer (-30 °C) for 24 h. The mixture was diluted
with Et2O (2 mL) and allowed to reach 0 °C. After the addition of
NaBH4 (400 mg, 10.6 mmol), the reaction was stirred for 15 min
at this temperature and poured into half-saturated aqueous NH4Cl
(50 mL). After 30 min, the mixture was extracted with Et2O (3 ×
50 mL), and the combined organic layers were dried over anhydrous
Na2SO4. Evaporation of the solvent afforded the crude product as
a colorless oil. The byproduct, 4-tert-butyldimethylsilyloxybutan-
1-ol, was recovered by Kugelrohr distillation (100 °C, 0.2 mbar).
The residue was purified by flash chromatography (50% Et2O/
pentane) on SiO2 to afford 2a (218 mg, 0.43 mmol, 85%) as a
SCHEME 9. Removal of PMP and the Unexpected
Cleavage of the C-N Bond
colorless oil. Rf 0.42 (50% Et2O/pentane); [R]25 -17.2 (c 0.98,
D
CHCl3); HPLC (Chiracel OD (4.6 × 250 mm); n-heptane/2-
propanol, 95:5; 1.0 mL‚min-1; λ ) 254 nm); major isomer, tR )
13.3 min; minor isomer, tR ) 5.9 min; 1H NMR (300 MHz, CDCl3)
δ 6.78 (d, J ) 8.9 Hz, 2H), 6.62 (d, J ) 8.9 Hz, 2H), 3.80-3.55
(m, 9H), 3.41 (m, 1H), 2.01 (m, 1H), 1.70-1.48 (m, 6H), 0.91 (s,
9H), 0.89 (s, 9H), 0.08 (s, 6H), 0.03 (s, 6H); 13C NMR (75 MHz,
CDCl3) δ 152.4, 141.7, 115.5 (2C), 114.9 (2C), 64.4, 62.7, 61.7,
58.0, 55.7, 40.1, 30.5, 29.8, 27.7, 25.9 (6C), 18.2 (2C), -5.4 (2C),
-5.5 (2C); IR (CHCl3) 3378, 2932, 2891, 2858, 1513, 1468, 1251,
1098, 1043, 836, 776 cm-1; HRMS calcd for C27H53NO4Si2 (M+),
511.3515; found, 511.3513. Anal. Calcd for C27H53NO4Si2: C,
63.35; H, 10.44; N, 2.74. Found: C, 62.91; H, 10.26; N, 3.17.
Epimer: colorless oil; Rf 0.44 (50% Et2O/pentane); [R]25D -3.2 (c
0.81, CHCl3); HPLC (Chiracel OD (4.6 × 250 mm); n-heptane/
2-propanol, 95:5; 1.0 mL‚min-1; λ ) 254 nm); major isomer, tR )
7.6 min; minor isomer, tR ) 5.9 min; 1H NMR (300 MHz, CDCl3)
δ 6.75 (d, J ) 8.9 Hz, 2H), 6.56 (d, J ) 8.9 Hz, 2H), 3.80-3.45
(m, 9H), 3.39-3.30 (m, 1H), 1.82-1.93 (m, 1H), 1.79-1.43 (m,
6H), 0.89 (s, 9H), 0.88 (s, 9H), 0.06 (s, 6H), 0.03 (s, 6H); 13C
NMR (75 MHz, CDCl3) δ 151.8, 142.3, 115.0 (2C), 114.6 (2C),
64.0, 62.9, 62.3, 57.2, 55.8, 42.0, 31.9, 29.3, 28.4, 25.9 (6C), 18.3,
18.2, -5.3 (2C), -5.5 (2C); IR (CHCl3) 3391, 2933, 2859, 1514,
protocol, oxidation occurred at the benzylic position leading to
the corresponding amino ketone 19 (eq 2).
Conclusion
Employing our newly developed CDI-mediated ring closure,
we have synthesized a variety of N-heterocycles, ranging from
azetidines to piperidines. We have further shown that the initial
products can be easily converted into drug-like molecules. In
combination with the rapidly expanding repertoire of enanti-
oselective Mannich reactions, this strategy will provide access
to structurally diverse PMP-protected N-heterocycles. We are
currently trying to apply this methodology to the synthesis of
small alkaloid natural products and an azetidine library for
screening purposes.
1468, 1251, 1097, 1042, 836, 774 cm-1
.
(2S,3R)-6-(tert-Butyldimethylsilyloxy)-2-[(3-tert-butyldimeth-
ylsilyloxy)propyl]-3-(4-methoxyphenylamino)-heptan-1-ol (2b).
Experimental Section
Colorless oil; Rf 0.40 (50% Et2O/pentane); [R]25 -20.1 (c 0.80,
D
The amino alcohols 2f-h have been described previously.8h The
compounds 2c, 2i, and 2j were prepared according to refs 7 and
8h. The spectroscopic data of the minor diastereomers are given,
although their absolute configurations were not determined.
Preparation of (2S,3R)-6-(tert-Butyldimethylsilyloxy)-2-[(2-
tert-butyldimethylsilyloxy)ethyl]-3-(4-methoxyphenylamino)-
hexan-1-ol (2a). To a stirred solution (-40 °C) of L-proline (17.3
mg, 0.15 mmol) and p-anisidine (61.6 mg, 0.5 mmol) in MeCN (5
mL) was added 4-tert-butyldimethylsilyloxybutanal (809 mg, 4
CHCl3); HPLC (Chiracel OD-H (4.6 × 250 mm); n-heptane/2-
propanol, 98:2; 0.7 mL‚min-1; λ ) 254 nm); major isomer, tR )
63.4 min; minor isomer, tR ) 25.0 min; 1H NMR (300 MHz,
CDCl3) δ 6.81-6.74 (m, 2H), 6.70-6.62 (m, 2H), 3.75 (br s, 5H),
3.70-3.52 (m, 4H), 3.48-3.39 (m, 1H), 3.21 (br s, 2H), 1.89-
1.24 (m, 11H), 0.91 (s, 9H), 0.87 (s, 9H), 0.06 (s, 6H), 0.01 (s,
6H); 13C NMR (75 MHz, CDCl3) δ 152.8, 141.7, 116.1 (2C), 114.9
(2C), 64.7, 63.1, 62.9, 58.8, 55.7, 41.6, 32.8, 31.5, 31.0, 26.0 (6C),
23.2, 22.2, 18.3 (2C), -5.3 (4C); IR (capillary) 3376, 2933, 2859,
4150 J. Org. Chem., Vol. 71, No. 11, 2006

N,N′-Carbonyldiimidazole-Mediated Cyclization
1512, 1467, 1250, 1100, 1043, 837, 777 cm-1; HRMS calcd for
C29H57NO4Si2 (M+), 539.3826; found, 539.3826; Anal. Calcd for
C29H57NO4Si2: C, 64.51; H, 10.64; N, 2.59. Found: C, 64.28; H,
10.79; N, 2.34. Epimer: colorless oil; Rf 0.40 (50% Et2O/pentane);
3.64 (m, 4H), 2.07-1.96 (m, 1H), 1.81-1.37 (m, 4H); 13C (75
MHz, CDCl3) δ 152.2, 141.5, 141.3, 128.4 (2C), 127.1 (2C), 126.9,
115.2 (2C), 114.7 (2C), 104.4, 64.9, 64.8, 63.7, 31.5, 55.7, 46.3,
31.6, 20.3; IR (KBr) 3314, 3193, 2949, 2880, 1510, 1479, 1409,
1286, 1256, 1232, 865, 1030, 818, 700 cm-1; Anal. Calcd for
C21H27NO4: C, 70.56; H, 7.61; N, 3.92. Found C, 70.42; H, 8.05;
N, 3.70.
[R]25 -1.3 (c 0.1, CHCl3); HPLC (Chiracel OD-H (4.6 × 250
D
mm); n-heptane/2-propanol, 98:2; 0.7 mL‚min-1; λ ) 254 nm);
1
major isomer, tR ) 42.6 min; minor isomer, tR ) 27.6 min; H
NMR (300 MHz, CDCl3) δ 6.78-6.72 (m, 2H), 6.63-6.58 (m,
2H), 6.86-6.79 (m, 1H), 6.74 (s, 3H), 6.73-6.64 (m, 1H), 3.61-
3.52 (m, 4H), 3.39-3.30 (m, 1H), 3.20 (br s, 1H), 1.74-1.24 (m,
11H), 0.89 (s, 9H), 0.87 (s, 9H), 0.02 (s, 6H), 0.00 (s, 6H); 13C
NMR (75 MHz, CDCl3) δ 152.3, 142.2, 115.5 (2C), 114.9 (2C),
64.4, 63.2, 62.9, 58.2, 55.8, 43.0, 32.9, 32.5, 30.4, 26.0, (6C), 24.8,
21.9, 18.3 (2C), -5.3 (4C); IR (CHCl3) 3394, 2932, 2859, 1513,
(S)-4-(1,3-Dioxolan-2-yl)-2-((S)-(4-fluorophenyl)(4-methoxy-
phenylamino)methyl)butan-1-ol (2j). Colorless solid; mp 89-91
°C; [R]24D +1.37 (c 1.02, CHCl3); 1H NMR (400 MHz, CDCl3) δ
7.21 (ddd, J ) 2.0, 5.0, 6.2 Hz, 2H), 6.91 (t, J ) 8.2 Hz, 2H), 6.61
(d, J ) 8.5 Hz, 2H), 6.43 (d, J ) 8.8 Hz, 2H), 4.72 (t, J ) 4.4 Hz,
1H), 4.45 (d, J ) 3.0 Hz, 1H), 3.85 (m, 2H), 3.75 (m, 2H), 3.61
(m, 5H), 1.85 (m, 1H), 1.61 (m, 2H), 1.43 (m, 2H); 13C NMR (100
MHz, CDCl3) δ 162.9 and 160.5 (J ) 244.0 Hz), 152.2, 141.0,
137.0, 128.7 and 128.6 (2C, J ) 8.4 Hz), 115.4 and 115.2 (2C, J
) 12.9 Hz), 115.1 (2C), 114.7 (2C), 104.4, 65.0, 64.9, 63.6, 61.0,
55.8, 46.3, 31.6, 20.4; 19F NMR (376 MHz, CDCl3) δ -116.0; IR
1468, 1250, 1100, 1042, 837, 776 cm-1
.
(S)-5-(tert-Butyldimethylsilyloxy)-2-((S)-(4-methoxyphenyl-
amino)(phenyl)methyl)pentan-1-ol (2c). Colorless foam; Rf 0.35
(25% EtOAc/pentane); [R]25D -20.0 (c 0.50, CHCl3); 1H NMR (400
MHz, CDCl3) δ 7.35-7.27 (m, 4H), 7.24-7.19 (m, 1H), 6.68 (d,
J ) 8.9 Hz, 2H), 6.51 (d, J ) 8.9 Hz, 2H), 4.56 (d, J ) 4.2 Hz,
1H), 3.70-3.67 (m, 5H), 3.60-3.53 (m, 1H), 2.05-1.96 (m, 1H),
1.66-1.29 (m, 4H), 0.88 (s, 9H), 0.03 (s, 6H); 13C NMR (100 MHz,
CDCl3) δ 152.0, 141.4, 141.3, 128.7 (2C), 127.0 (2C), 126.8, 115.1
(2C), 114.6 (2C), 64.0, 63.1, 61.4, 55.7, 46.3, 30.7, 26.0 (3C), 22.5,
18.4, -5.2 (2C); IR (KBr) 3309, 3186, 2936, 2856, 1513, 1473,
1247, 1105, 1036, 835, 776, 706 cm-1; HRMS calcd for C25H39-
NO3Si (M+), 429.2699; found, 429.2697. Epimer: colorless solid;
Rf 0.35 (25% EtOAc/pentane); 1H NMR (400 MHz, CDCl3) δ
7.30-7.27 (m, 4H), 7.23-7.17 (m, 1H), 6.66 (d, J ) 8.9 Hz, 2H),
6.50 (d, J ) 8.0 Hz, 2H), 4.34 (d, J ) 6.1 Hz, 1H), 3.80 (dd, J )
11.8, 2.8 Hz, 1H), 3.70 (dd, J ) 11.4, 5.8 Hz, 1H), 3.68 (s, 3H),
3.55 (t, J ) 5.9 Hz, 2H), 1.97-1.87 (m, 1H), 1.65-1.34 (m, 4H),
0.86 (s, 9H), 0.01 (s, 3H), 0.00 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ 152.3, 142.2, 140.7, 128.4 (2C), 126.9 (3C), 115.8 (2C),
114.6 (2C), 63.8 (2C), 63.2, 55.7, 45.9, 30.3, 26.0 (3C), 25.2, 18.4,
-5.2 (2C); IR (CHCl3) 3421, 3293, 2933, 2863, 1512, 1466, 1284,
(CHCl3) 3309, 2930, 2878, 1512, 1244, 1141, 1033, 820 cm-1
.
Anal. Calcd for C21H26FNO4: C, 67.18; H, 6.98; N, 3.73. Found:
C, 67.31; H, 6.82; N, 3.74.
(2S,3R)-7-(tert-Butyldimethylsilyloxy)-2-(3-(tert-butyldimeth-
ylsilyloxy)propyl)-3-(4-methoxyphenylamino)heptyl 1H-Imida-
zole-1-carboxylate (3). Colorless oil; Rf 0.15 (50% Et2O/pentane);
1
[R]25 -6.8 (c 0.53, CHCl3); H NMR (300 MHz, CDCl3) δ 8.09
D
(s, 1H), 7.38 (s, 1H), 7.07 (s, 1H), 6.72 (d, J ) 8.9 Hz, 2H), 6.50
(d, J ) 8.3 Hz, 2H), 4.43 (d, J ) 5.5 Hz, 2H), 3.72 (s, 3H), 3.64
(t, J ) 5.7 Hz, 2H), 3.56 (t, J ) 6.0 Hz, 2H), 3.47 (m, 1H), 3.15
(br s, 1H), 2.13 (m, 1H), 1.70-1.30 (m, 6H), 0.89 (s, 9H), 0.86 (s,
9H), 0.50 (s, 6H), 0.00 (s, 6H); 13C NMR (75 MHz, CDCl3) δ
151.9, 148.6, 141.9, 136.9, 130.6, 116.9, 115.0 (2C), 114.1 (2C),
68.8, 62.8, 62.7, 55.7, 55.0, 40.4, 32.6, 31.9, 30.9, 25.9 (6C), 23.4,
23.3, 18.3, 18.2, -5.4 (4C); IR (CHCl3) 3322, 3129, 2933, 2858,
1764, 1514, 1469, 1403, 1317, 1242, 1176, 1100, 837, 775, 652
cm-1; HRMS calcd for C33H59N3O5Si2 (M+), 633.3993; found,
633.3993.
1232, 1103, 1038, 834, 779, 743, 703 cm-1
.
General Procedure for the Preparation of the Azetidines 5.
A solution of the corresponding amino alcohol (0.2 mmol) and 1,1′-
carbonyldiimidazole (0.4 mmol) in MeCN (10 mL) was refluxed
for 2 h. The solvent was evaporated in vacuo, and the intermediate
carbamates were heated to 150 °C in a Kugelrohr oven under high
vacuum (0.1 mbar) for 2 h. Products of lower molecular weight
were collected in the receiving flask. The residue was purified by
flash chromatography on silica gel to afford the azetidines.
(2S,3R)-3-(2-(tert-Butyldimethylsilyloxy)ethyl)-2-(3-(tert-bu-
tyldimethylsilyloxy)propyl)1-(4-methoxyphenyl)-azetidine (5a).
(3S,4R)-3-(Hydroxymethyl)-4-(4-methoxyphenylamino)hep-
tane-1,7-diyl diacetate (2d). Colorless oil; HPLC (Daicel AD (4.6
× 250 mm); 2-propanol/n-heptane, 1:10; 0.7 mL‚min-1; λ ) 230
nm); major enantiomer, tR ) 44.3 min; minor enantiomer, tR
)
48.1 min; [R]25 -12.2 (c 0.14, CHCl3); 1H NMR (300 MHz,
D
CDCl3) δ 6.80-6.84 (m, 2H), 6.65-6.60 (m, 2H), 4.22-3.99 (m,
4H), 3.76-3.74 (m, 5H), 3.54-3.52 (m, 1H), 2.05 (s, 3H), 2.03
(s, 3H), 1.96-1.81 (m, 1H), 1.80-1.50 (m, 6H); 13C NMR (75
MHz, CDCl3) δ 171.1, 171.0, 152.6, 141.6, 115.5 (2C), 115.0 (2C),
64.2, 63.9, 62.9, 57.3, 55.7, 39.5, 28.6, 26.0, 25.6, 20.9 (2C); IR
Colorless oil; Rf 0.50 (17% Et2O/pentane); [R]25 -95.6 (c 0.96,
D
(CHCl3) 3506, 3394, 2951, 1733, 1514, 1465, 1368, 823, 757 cm-1
.
CHCl3); 1H NMR (300 MHz, CDCl3) δ 6.80 (d, J ) 9.0 Hz, 2H),
6.52 (d, J ) 9.0 Hz, 2H), 3.95 (q, J ) 7.7, 1 Hz), 3.75 (s, 3H),
3.74-3.55 (m, 6H), 2.72-2.57 (m, 1H), 2.06-1.80 (m, 4H), 1.60
(3R*,4R*)-3-(Hydroxymethyl)-4-(4-methoxyphenylamino)-
heptane-1,7-diyl diacetate (2e). Colorless oil; HPLC ((S,S)-
(m, 2H), 0.92 (s, 9H), 0.91 (s, 9H), 0.08 (s, 6H), 0.07 (s, 6H); 13
C
Whelk01 (4.6 × 250 mm); ethanol/n-heptane, 1:10; 0.5 mL‚min-1
;
NMR (75 MHz, CDCl3) δ 152.3, 147.1, 114.5 (2C), 113.4 (2C),
66.2, 62.8, 61.4, 56.7, 55.7, 32.4, 30.1, 29.5, 27.4, 25.9 (6C), 18.3
(2C), -5.3 (2C), -5.4 (2C); IR (capillary) 2933, 2896, 2857, 1513,
1469, 1244, 1101, 836, 777 cm-1; HRMS calcd for C27H51NO3Si2
(M+), 493.3407; found, 493.3408.
λ ) 254 nm); major enantiomer, tR ) 57.1 min; minor enantiomer,
tR ) 53.5 min; [R]25D -6.4 (c 0.81, CHCl3); 1H NMR (300 MHz,
CDCl3) δ 6.78-6.73 (m, 2H), 6.61-6.50 (m, 2H), 4.10-3.99 (m,
4H), 3.90-3.82 (m, 1H), 3.74 (s, 3H), 3.73-3.64 (m, 1H), 3.53-
3.43 (m, 2H), 2.92 (br s, 1H), 2.03 (s, 3H), 2.00 (s, 3H), 1.90-
1.46 (m, 6H); 13C NMR (75 MHz, CDCl3) δ 171.2, 171.1, 152.2,
141.7, 115.0 (2C), 114.8 (2C), 64.2, 63.2, 62.8, 56.2, 55.8, 40.0,
28.7, 27.3, 25.4, 20.9 (2C); IR (CHCl3) 3499, 3397, 3018, 2955,
1732, 1513, 1465, 1368, 1241, 1039, 822, 757 cm-1; HRMS calcd
for C19H29NO6 (M+), 367.1995; found, 349.1993.
(2S,3R)-2-(4-(tert-Butyldimethylsilyloxy)butyl)-3-(3-(tert-bu-
tyldimethylsilyloxy)propyl)1-(4-methoxyphenyl)-azetidine (5b).
Colorless oil; Rf 0.40 (17% Et2O/pentane); [R]25 -55.0 (c 0.76,
D
CHCl3); 1H NMR (300 MHz, CDCl3) δ 6.80 (d, J ) 8.8 Hz, 2H),
6.50 (m, 2H), 3.89 (m, 1H), 3.75 (s, 3H), 3.68-3.56 (m, 6H), 2.58-
2.42 (m, 1H), 1.90-1.28 (m, 10H), 0.91 (s, 18H), 0.06 (s, 12H);
13C NMR (75 MHz, CDCl3) δ 152.3, 147.2, 114.6 (2C), 113.5 (2C),
66.6, 63.2, 63.0, 56.8, 33.2, 33.1, 30.9, 30.8, 26.9 (6C), 25.7, 22.8,
18.4 (2C), -5.2 (4C); IR (CHCl3) 2933, 2858, 1511, 1468, 1245,
1102, 1044, 837, 777 cm-1; HRMS calcd for C29H55NO3Si2 (M+),
521.3721; found, 521.3721.
(S)-4-(1,3-Dioxolan-2-yl)-2-((S)-(4-methoxyphenylamino)(phen-
yl)methyl)butan-1-ol (2i). Colorless solid; Rf ) 0.35 (33% pentane/
25
Et2O); [R]
-23.8 (c 0.51, CDCl3); HPLC (Chiralpac AS (4.6
D
× 250 mm); n-heptane/2-PrOH, 7:3; 0.8 mL‚min-1; λ ) 230 nm);
1
major isomer, tR ) 8.33 min; minor isomer, tR ) 11.02 min; H
NMR (300 MHz, CDCl3) δ 7.33-7.26 (m, 4H), 7.24-7.17 (m,
1H), 6.70-6.64 (m, 2H), 6.53-6.40 (m, 2H), 4.79 (t, J ) 4.5 Hz,
1H), 4.53 (d, J ) 4.4 Hz, 1H), 3.95-3.79 (m, 1H), 3.70-
(2S,3R)-1-(4-Methoxyphenyl)-3-(3-(tert-butyldimethylsilyloxy)-
propyl)-2-phenylazetidine (5c). Colorless oil; Rf 0.50 (9% Et2O/
J. Org. Chem, Vol. 71, No. 11, 2006 4151

de Figueiredo et al.
1
pentane); [R]25 -103.3 (c 0.26, CHCl3); H NMR (300 MHz,
(300 MHz, CDCl3) δ 7.36-7.25 (m, 5H), 6.75-6.72 (m, 2H),
6.38-6.35 (m, 2H), 5.00-4.98 (m, 1H), 4.69-4.66 (m, 1H), 3.87-
3.65 (m, 9H), 2.75 (m, 1H), 1.53-1.31 (m, 4H); 13C (75 MHz,
CDCl3) δ 152.3, 146.3, 139.3, 128.2 (2C), 127.1, 126.9 (2C), 114.5
(2C), 113.3 (2C), 104.3, 69.2, 64.7, 55.8, 55.2, 35.4, 31.5, 25.2;
IR (CHCl3) 2952, 1511, 1241, 1136, 1038, 756, 704 cm-1. Anal.
Calcd for C21H25NO3: C, 74.31; H, 7.24; N, 4.13. Found: C, 73.90;
H, 7.45; N, 3.81.
D
CDCl3) δ 7.40-7.24 (m, 5H), 6.85 (d, J ) 8.9 Hz, 2H), 6.35 (d,
J ) 8.9 Hz, 2H), 5.01 (d, J ) 8.3 Hz, 1H), 3.80 (t, J ) 7.1 Hz,
1H), 3.74 (s, 3H), 3.65 (dd, J ) 6.7, 3.0 Hz, 1H), 3.46 (t, J ) 6.2
Hz, 2H), 2.80-2.65 (m, 1H), 1.50-1.10 (m, 4H), 0.84 (s, 9H),
-0.03 (s, 3H), -0.04 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 152.2,
146.4, 139.5, 128.1 (2C), 127.0, 126.9 (2C), 114.5 (2C), 113.3 (2C),
69.4, 63.0, 55.8, 55.3, 35.4, 30.3, 27.1, 25.9 (3C), 18.3, -5.4 (2C);
IR (CHCl3) 3003, 2950, 2856, 1511, 1470, 1242, 1100, 1043, 834,
758 cm-1; HRMS calcd for C25H37NO2Si (M+), 411.2593; found,
411.2595.
(2S,3R)-3-(2-(1,3-Dioxolan-2-yl)ethyl)-2-(4-fluorophenyl)-1-(4-
methoxyphenyl)azetidine (5j). Colorless solid; mp 85-88 °C; Rf
1
0.66 (Et2O); [R]24 -6.94 (c 1.11, CHCl3); H NMR (300 MHz,
D
3-((2R,3R)-3-(2-Acetoxyethyl)-1-(4-methoxyphenyl)azetidin-
2-yl)propyl acetate (5d). Colorless oil; Rf 0.32 (50% Et2O/pentane);
[R]25D -72.0 (c 0.83, CHCl3); 1H NMR (500 MHz, CDCl3) δ 6.80
(d, J ) 8.9 Hz, 2H), 6.49 (d, J ) 8.9 Hz, 2H), 4.15-4.07 (m, 4H),
3.95 (q, J ) 6.6 Hz, 1H), 3.75 (s, 3H), 3.65 (dd, J ) 3.5, 7.1 Hz,
1H), 3.61 (t, J ) 7.5 Hz, 1H), 2.61 (m, 1H), 2.15-2.08 (m, 1H),
2.07 (s, 3H), 2.06 (s, 3H), 2.05-1.96 (m, 1H), 1.88-1.82 (m, 2H),
1.70-1.66 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 171.1 (2C),
152.6, 146.6, 114.6 (2C), 113.5, 65.5, 64.2, 62.7, 56.3, 55.7, 30.1,
28.4, 27.5, 25.4, 20.9; IR (CHCl3) 2953, 2847, 1739, 1511, 1468,
1367, 1241, 1040, 822 cm-1; HRMS calcd for C19H27NO5 (M+),
349.1889; found, 349.1890.
CDCl3) δ 7.27 (ddd, J ) 3.0, 5.4, 8.4 Hz, 2H), 6.96 (t, J ) 8.8 Hz,
2H), 6.67 (dd, J ) 2.2, 6.7 Hz, 2H), 6.30 (dd, J ) 2.2, 6.7 Hz,
2H), 4.89 (d, J ) 8.4 Hz, 1H), 4.62 (t, J ) 4.6 Hz, 1H), 3.80 (m,
2H), 3.71 (m, 2H), 3.64 (s, 3H), 3.59 (d, J ) 3.2 Hz, 1H), 3.57 (d,
J ) 3.0 Hz, 1H), 2.66 (m, 1H), 1.43 (m, 2H), 1.25 (m, 2H); 13C
NMR (75 MHz, CDCl3) δ 163.6 and 160.3 (J ) 245.0 Hz), 152.3,
145.9, 134.9, 128.4 and 128.3 (2C, J ) 8.0 Hz), 115.1 and 114.9
(2C, J ) 21.7 Hz), 114.4 (2C), 113.2 (2C), 104.1, 68.4, 64.6 (2C),
55.6, 55.0, 35.2, 31.3, 25.0; 19F NMR (376 MHz, CDCl3) δ -115.8;
IR (CHCl3) 2940, 2848, 1509, 1239, 1038, 817 cm-1. Anal. Calcd
for C21H24FNO3: C, 70.57; H, 6.77; N, 3.92. Found: C, 70.38; H,
6.48; N, 3.80.
3-((2R*,3S*)-3-(2-Acetoxyethyl)-1-(4-methoxyphenyl)azetidin-
2-yl)propyl acetate (5e). Colorless oil; Rf 0.32 (50% Et2O/pentane);
[R]25D -16.8 (c 0.41, CHCl3); 1H NMR (300 MHz, CDCl3) δ 6.80
(d, J ) 8.9 Hz, 2H), 6.46 (d, J ) 8.9 Hz, 2H), 4.15-4.01 (m, 5H),
3.75 (s, 3H), 3.66-3.58 (m, 1H), 3.20 (t, J ) 7.0 Hz, 1H), 2.55-
2.41 (m, 1H), 2.06 (s, 3H), 2.05 (s, 3H), 2.00-1.66 (m, 6H); 13C
NMR (75 MHz, CDCl3) δ 171.1, 171.0, 152.4, 146.7, 114.7 (2C),
113.0 (2C), 70.1, 64.4, 62.5, 56.5, 55.8, 34.2, 33.3, 32.4, 24.1, 21.0,
20.9; IR (CHCl3) 2950, 1738, 1511, 1241, 1040, 757 cm-1; HRMS
calcd for C19H27NO5 (M+), 349.1889; found, 349.1889.
Preparation of (R)-1-(4-Fluorophenyl)-3-((2S,3R)-2-(4-fluo-
rophenyl)-1-(4-methoxyphenyl)azetidin-3-yl)propan-1-ol and (S)-
1-(4-Fluorophenyl)-3-((2S,3R)-2-(4-fluorophenyl)-1-(4-methoxy-
phenyl)azetidin-3-yl)propan-1-ol (6). To a solution of 5j (0.31 g,
0.86 mmol) in THF (5 mL) was added a solution of 2 N HCl (3
mL). The mixture was stirred for 4 h at room temperature. The
mixture was quenched with a solution of NaHCO3 and then
extracted three times with CH2Cl2 (5 mL). The combined organic
layers were dried with Na2SO4. Removal of the solvent on a rotary
evaporator and filtration on Celite with CH2Cl2 gave the aldehyde
as a yellow oil, which was used without purification in the next
step. To a cold solution of the aldehyde (0.25 g, 0.8 mmol) in THF
(8 mL) at -70 °C was added over 5 min (4-fluorophenyl)-
magnesium bromide (1.2 mL, 1 M solution in THF, 1.2 mmol).
After 2 h of stirring at -70 °C, the reaction mixture was allowed
to warm to room temperature and stirred overnight. The reaction
was quenched with water and extracted with CH2Cl2 (3 × 10 mL).
The organic fractions were combined and washed successively with
water and brine. After drying (Na2SO4), filtration, and concentration,
the crude compound was chromatographed on silica gel (pentane/
AcOEt, 7:3) to give 6 (0.243 g, 0.59 mmol, 75%) as a colorless
solid. Less polar diastereomer: mp 108-111 °C; Rf 0.59 (25%
Et2O/pentane); [R]25D -34.09 (c 1.03, CHCl3); HPLC (LI60.M (250
× 4 mm); pentane/Et2O, 6:4; 0.5 mL‚min-1; λ ) 254 nm); major
(2R,3R)-2-Ethyl-1-(4-methoxyphenyl)-3-methylazetidine (5f).
Colorless oil; Rf 0.29 (9% Et2O/pentane); [R]25 -146.5 (c 1.04,
D
CHCl3); 1H NMR (400 MHz, CDCl3) δ 6.80 (d, J ) 8.9 Hz, 2H),
6.51 (d, J ) 8.9 Hz, 2H), 3.77 (m, 1H), 3.75 (s, 3H), 3.62 (dd, J
) 8.0, 6.8 Hz, 1H), 3.48 (dd, J ) 6.8, 3.2 Hz, 1H), 2.65 (m, 1H),
1.83 (m, 2H), 1.30 (d, J ) 7.2 Hz, 3H), 0.92 (t, J ) 7.5 Hz, 3H);
13C NMR (75 MHz, CDCl3) δ 152.2, 147.4, 114.5 (2C), 113.5 (2C),
67.9, 58.1, 55.7, 27.5, 23.8, 14.7, 10.2; IR (capillary) 2961, 2873,
2834, 1511, 1465, 1293, 1240, 1120, 1041, 819 cm-1; HRMS calcd
for C13H19NO (M+), 205.1467; found, 205.1467.
(2R,3R)-3-Ethyl-1-(4-methoxyphenyl)-2-propylazetidine (5g).
Colorless oil; Rf 0.50 (17% Et2O/pentane); [R]25D -170.0 (c 0.90,
CHCl3); 1H NMR (300 MHz, CDCl3) δ 6.81 (d, J ) 9.0 Hz, 2H),
6.52 (d, J ) 9.0 Hz, 2H), 3.89 (dt, J ) 8.4, 4.4 Hz, 1H), 3.76 (s,
3H), 3.61-3.56 (m, 2H), 2.48-2.32 (m, 1H), 1.65-1.65 (m, 4H),
1.43-1.29 (m, 2H), 1.00 (t, J ) 7.2 Hz, 3H), 0.93 (t, J ) 7.4 Hz,
3H); 13C NMR (75 MHz, CDCl3) δ 152.2, 147.4, 114.5 (2C), 113.4
(2C), 66.4, 56.5, 55.7, 35.2, 33.3, 22.3, 19.7, 14.3, 11.7; IR
1
isomer, tR ) 12.5 min; minor isomer, tR ) 11.3 min; H NMR
(400 MHz, CDCl3) δ 7.23 (td, J ) 2.6, 8.0 Hz, 2H), 7.08 (td, J )
2.5, 8.2 Hz, 2H), 6.93 (m, 4H), 6.65 (d, J ) 8.8 Hz, 2H), 6.24 (d,
J ) 8.5 Hz, 2H), 4.87 (d, J ) 8.0 Hz, 1H), 4.38 (t, J ) 5.7 Hz,
1H), 3.68 (d, J ) 4.5 Hz, 1H), 3.62 (s, 3H), 3.50 (d, J ) 4.9 Hz,
(capillary) 2956, 2867, 2835, 1510, 1464, 1240, 1042, 820 cm-1
HRMS calcd for C15H23NO (M+), 233.1780; found, 233.1780.
;
1H), 2.62 (m, 1H), 1.67 (m, 1H), 1.32 (m, 1H), 1.25 (m, 2H); 13
C
(2S,3R)-1-(4-Methoxyphenyl)-3-methyl-2-phenylazetidine (5h).
NMR (100 MHz, CDCl3) δ 163.2 and 160.8 (2C, J ) 244.0 Hz),
152.3, 145.9, 140.2, 135.0, 128.6 and 128.5 (2C, J ) 7.6 Hz), 127.3
and 127.2 (2C, J ) 8.4 Hz), 115.3 and 115.2 (2C, J ) 8.4 Hz),
115.1 and 115.0 (2C, J ) 8.4 Hz), 114.6 (2C), 113.3 (2C), 73.9,
68.6, 55.9, 55.3, 36.9, 35.6, 27.2; 19F NMR (376 MHz, CDCl3) δ
-115.0, -115.5; IR (CHCl3) 3378, 3014, 2939, 2852, 1509, 1225,
757 cm-1; HRMS calcd for C25H25F2NO2 (M+), 409.1854; found,
Colorless oil; Rf 0.44 (9% Et2O/pentane); [R]25 -267.8 (c 0.84,
D
1
CHCl3); H NMR (400 MHz, CDCl3) δ 7.41-7.27 (m, 5H), 6.78
(d, J ) 9.0 Hz, 2H), 6.42 (d, J ) 9.0 Hz, 2H), 5.00 (d, J ) 8.3 Hz,
1H), 3.86 (dd, J ) 7.7, 6.7 Hz, 1H), 3.74 (s, 3H), 3.59 (dd, J )
6.6, 2.8 Hz, 1H), 2.88 (m, 1H), 0.93 (d, J ) 7.2 Hz, 3H); 13C NMR
(100 MHz, CDCl3) δ 152.1, 146.4, 139.6, 128.0 (2C), 126.8, 126.7
(2C), 114.5 (2C), 113.3 (2C), 69.5, 57.0, 55.8, 30.2, 16.2; IR
(capillary) 2965, 2932, 2875, 2802, 1447, 1406, 1247, 1140, 1107,
1081, 879, 859, 755, 692, 639, 552, 529, 505 cm-1; HRMS calcd
for C17H19NO (M+), 253.1467; found, 253.1467.
409.1853. More polar diastereomer: mp 100-104 °C; [R]25
D
1
-43.4 (c 1.07 CHCl3); H NMR (400 MHz, CDCl3) δ 7.23 (td, J
) 2.2, 6.0 Hz, 2H), 7.01 (td, J ) 3.2, 6.0 Hz, 2H), 6.91 (m, 4H),
6.64 (d, J ) 8.8 Hz, 2H), 6.24 (d, J ) 8.8 Hz, 2H), 4.86 (d, J )
8.0 Hz, 1H), 4.33 (t, J ) 6.0 Hz, 1H), 3.80 (d, J ) 4.4 Hz, 1H),
3.62 (s, 3H), 3.52 (d, J ) 4.4 Hz, 1H), 2.60 (m, 1H), 1.72 (m, 1H),
1.51 (m, 1H), 1.19 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 163.2
and 160.8 (2C, J ) 245.0 Hz), 152.4, 145.9, 140.2, 135.0, 128.6
and 128.5 (2C, J ) 7.6 Hz), 127.3 and 127.2 (2C, J ) 8.4 Hz),
(2S,3R)-3-(2-(1,3-Dioxolan-2-yl)ethyl)-1-(4-methoxyphenyl)-
2-phenylazetidine (5i). Colorless solid; Rf 0.35 (25% Et2O/pentane);
[R]25 -154.0 (c 0.83, CHCl3); HPLC (Chiralpac AS (4.6 × 250
D
mm); n-heptane/i-PrOH, 6:4; 0.7 mL‚min-1; λ )214 nm); major
1
isomer, tR ) 15.29 min; minor isomer, tR ) 10.56 min; H NMR
4152 J. Org. Chem., Vol. 71, No. 11, 2006

N,N′-Carbonyldiimidazole-Mediated Cyclization
115.3 and 115.2 (2C, J ) 5.3 Hz), 115.1 and 115.0 (2C, J ) 5.3
Hz), 114.6 (2C), 113.3 (2C), 73.9, 68.5, 55.9, 55.3, 36.9, 35.6, 27.2;
19F NMR (376 MHz, CDCl3) δ -115.1, -115.6; IR (CHCl3) 3346,
3010, 2942, 2855, 1509, 1227, 758 cm-1; HRMS calcd for
C25H25F2NO2 (M+), 409.1854; found, 409.1853.
(()-(2R*,4S*)-2-Butyl-1-(4-methoxyphenyl)-4-methylazeti-
dine (8a). Colorless oil; Rf 0.62 (9% Et2O/pentane); 1H NMR (300
MHz, CDCl3) δ 6.81 (d, J ) 9.0 Hz, 2H), 6.58 (d, J ) 9.0 Hz,
2H), 3.82-3.61 (m, 2H), 3.76 (s, 3H), 2.51 (dd, J ) 10.6, 8.0 Hz,
1H), 2.00-1.87 (m, 1H), 1.75-1.59 (m, 2H), 1.47 (d, J ) 6.1 Hz,
3H), 1.44-1.24 (m, 2H), 0.98 (t, J ) 7.3 Hz, 3H); 13C NMR (75
MHz, CDCl3) δ 152.4, 147,6, 114.6 (2C), 113.2 (2C), 61.1, 58.3,
55.8, 40.4, 32.2, 24.2, 18.2, 14.2; IR (capillary) 2958, 2928, 2862,
1510, 1242, 1042, 819 cm-1; HRMS calcd for C14H21NO (M+),
219.1623; found, 219.1624.
(()-(2S*,4S*)-2-Cyclohexyl-1-(4-methoxyphenyl)-4-methyl-
azetidine (8b). Colorless solid; Rf 0.49 (9% Et2O/pentane); 1H NMR
(300 MHz, CDCl3) δ 6.81-6.74 (m, 2H), 6.59-6.53 (m, 2H), 3.74
(s, 3H), 3.83-3.65 (m, 1H), 3.61-3.50 (m, 1H), 2.41-2.29 (m,
1H), 1.92-1.60 (m, 7H), 1.43 (d, J ) 6.1 Hz, 3H), 1.30-0.87 (m,
5H); 13C NMR (75 MHz, CDCl3) δ 152.3, 148.0, 114.6 (2C), 113.3
(2C), 66.1, 58.6, 55.8, 44.0, 29.8, 28.2, 27.2, 26.8, 26.4, 26.2, 24.0;
IR (CHCl3) 2925, 2852, 1509, 1242, 1042, 820, 758 cm-1; HRMS
calcd for C17H25NO (M+), 259.1936; found, 259.1936.
filtered, and evaporated in vacuo. Flash chromatography on silica
gel (50% Et2O/pentane) afforded 16 as a colorless oil: Rf 0.33 (50%
1
Et2O/pentane); [R]25 -6.2 (c 0.55, CHCl3); H NMR (500 MHz,
D
CDCl3) δ 7.65 (m, 2H), 7.59 (m, 2H), 7.45-7.33 (m, 6H), 6.84
(m, 2H), 6.50 (m, 2H), 3.77 (s, 3H), 3.65 (m, 2H), 3.57 (m, 1H),
3.50 (m, 2H), 3.33 (t, J ) 8.6 Hz, 1H), 3.07 (q, J ) 8.2 Hz, 1H),
2.31 (m, 1H), 2.13 (m, 1H), 1.83 (m, 1H), 1.74 (m, 1H), 1.65-
1.55 (m, 3H), 1.42 (m, 2H), 1.05 (s, 9H); 13C NMR (75 MHz,
CDCl3) δ 150.7, 142.1, 135.6 (2C), 135.5 (2C), 133.6, 133.5, 129.6
(2C), 127.7 (2C), 127.6 (2C), 115.1 (2C), 112.9 (2C), 65.4, 62.9,
60.7, 56.0, 47.2, 45.5, 29.4, 29.0, 26.8 (3C), 25.5, 19.2; IR (CHCl3)
3395, 3008, 2936, 2860, 1514, 1368, 1241, 1109, 1043, 817, 758,
705, 614, 505 cm-1; HRMS calcd for C31H41NO3Si (M+), 503.2856;
found, 503.2856.
((2S,3S)-1-(4-Methoxyphenyl)-2-phenylpiperidin-3-yl)metha-
nol (17). Tetra-n-butylammonium fluoride (1 M in THF, 1 mL, 1
mmol) was added to a solution of 2c (100 mg, 0.23 mmol) in THF
(5 mL) at ambient temperature. After 30 min, the reaction mixture
was filtered through a plug of silica eluting with Et2O. The filtrate
is evaporated to dryness, and a solution of this crude alcohol and
1,1′-carbonyldiimidazole (100 mg, 0.62 mmol) in MeCN (10 mL)
was refluxed for 2 h. The solvent was evaporated in vacuo, and
the residue was heated to 150 °C under high vacuum before it was
taken up in THF/2 N aq NaOH, 1:1 (10 mL). This mixture was
stirred for 2 h at room temperature. The aqueous layers were
extracted with Et2O (2 × 10 mL), and the combined organic layers
were dried with Na2SO4, filtered, and evaporated in vacuo. Flash
chromatography on silica gel (50% Et2O/pentane) afforded 17 in
60% yield as colorless oil: Rf 0.29 (50% Et2O/pentane); [R]25D +3.5
(()-(1R*,2R*)-2-((S*)-Phenyl(phenylamino)methyl)cyclohex-
anol (9). Prepared from (()-(R*)-2-((S*)-phenyl(phenylamino)-
methyl)cyclohexanone23 by reduction with excess NaBH4 in
1
methanol. Colorless solid; Rf 0.36 (33% Et2O/pentane); H NMR
(300 MHz, CDCl3) δ 7.35-7.15 (m, 5H), 7.09-7.01 (m, 2H),
6.61-6.44 (m, 3H), 4.45 (d, J ) 7.5 Hz, 1H), 4.01 (br s, 1H),
1.85-1.16 (m, 10H); 13C NMR (75 MHz, CDCl3) δ 147.6, 142.8,
129.1 (2C), 128.4 (2C), 126.9 (2C), 126.7 (2C), 116.7, 113.2, 66.9,
61.1, 47.5, 34.1, 25.9, 25.3, 20.1; IR (KBr) 3544, 3369, 2923, 2857,
1605, 1504, 1312, 974, 750, 699 cm-1. Anal. Calcd for C19H23-
NO: C, 81.10; H, 8.24; N, 4.98. Found: C, 81.22; H, 8.31; N,
4.91.
1
(c 0.20, CHCl3); H NMR (300 MHz, CDCl3) δ 7.29-7.24 (m,
2H), 7.21-7.06 (m, 3H), 6.93 (d, J ) 9.0 Hz, 2H), 6.65 (d, J )
9.0 Hz, 2H), 3.86 (d, J ) 8.7 Hz, 1H), 3.68 (s, 3H), 3.46 (dd, J )
10.9, 4.4 Hz, 1H), 3.36-3.25 (m, 2H), 2.89 (ddd, J ) 11.8, 10.2,
4.3 Hz, 1H), 2.05-1.83 (m, 4H), 1.55-1.40 (m, 1H), 1.27 (br s,
1H); 13C NMR (75 MHz, CDCl3) δ 155.1, 146.0, 142.1, 128.4 (2C),
128.0 (2C), 126.7, 125.1 (2C), 113.6 (2C), 67.4, 65.2, 56.6, 55.2,
45.9, 27.4, 25.5; IR (CHCl3) 3396, 3007, 2935, 2835, 2795, 2706
(w, “Bohlmann band”), 1509, 1453, 1241, 1036, 833, 760, 703
cm-1; HRMS calcd for C19H23NO2 (M+), 279.1729; found,
279.1729.
(3S,4R)-3-(tert-Butyldiphenylsilyloxy)methyl-4-(4-methoxy-
phenylamino)-heptane-1,7-diol (15). Imidazole (310 mg, 4.56
mmol) and tert-butyldiphenylsilylchloride (1.00 g, 3.65 mmol) were
added to a solution of 5a (1.60 g, 3.04 mmol) in DMF (20 mL) at
ambient temperature. After 2 h, the solution was diluted with ether
(200 mL), washed with saturated aqueous NaHCO3 (2 × 100 mL),
dried (MgSO4), and evaporated to dryness. The residue was filtered
over a plug of silica, eluting with 10% ether/pentane. The filtrate
was concentrated and dissolved in MeOH (10 mL). A catalytic
amount of p-toluenesulfonic acid was added, and the solution was
stirred at ambient until TLC analysis revealed complete conversion
to the product. The reaction mixture was diluted with EtOAc and
extracted with saturated aqueous NaHCO3, dried (MgSO4), and
evaporated to dryness. Flash chromatography (EtOAc) afforded the
tile compound (1.33 g, 84%, two steps) as colorless oil: Rf 0.43
Preparation of (2R,3R)-tert-Butyl 3-ethyl-2-propylazetidine-
1-carboxylate (18). CAN (2.45 g, 4.48 mmol) was added to a
solution of 5g (262 mg, 1.12 mmol) in a 3:1 mixture of MeCN/
H2O (28 mL) at ambient temperature. After 30 min, NaOH (1M)
was added, and the mixture was extracted four times with CH2Cl2.
The organic layers were combined, washed with brine, filtered
through cotton, and concentrated to dryness. Di-tert-butyl carbonate
(489 mg, 2.24 mmol) was added to the residue, and the resulting
mixture was dissolved in a 2:1 mixture of PhMe/H2O (6 mL).
Sodium hydroxide (270 µL, 25 wt %, 1.68 mmol) was added, and
the mixture was stirred at ambient temperature for 3 h. The reaction
mixture was diluted with H2O and extracted twice with ethyl acetate.
The organic layers were combined, washed with brine, dried over
MgSO4, filtered, and concentrated to dryness. The residue was
purified by flash chromatography (25% Et2O/pentane) to afford the
title compound as a colorless oil (183 mg, 72%, two steps): Rf
0.20 (17% Et2O/pentane); [R]25D -108.8 (c 0.57, CHCl3); 1H NMR
(300 MHz, CDCl3) δ 4.16 (q, J ) 7.6 Hz, 1H), 3.91 (t, J ) 8.5
Hz, 1H), 3.40 (dd, J ) 8.3, 5.7 Hz, 1H), 2.50-2.35 (m, 1H), 1.65-
1.15 (m, 6H), 1.42 (s, 9H), 0.91 (t, J ) 7.3 Hz, 3H), 0.81 (t, J )
7.3 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 157.0, 79.0, 64.0,
53.0, 34.6, 32.6, 28.5 (3C), 21.9, 19.9, 14.3, 11.6; IR (CHCl3) 2962-
(s), 2876, 1703, 1390, 1364, 1143 cm-1; HRMS calcd for C13H25-
NO2 (M+), 227.1885; found, 227.1886.
(EtOAc); [R]25 +21.3 (c 0.74, CHCl3); 1H NMR (300 MHz,
D
CDCl3) δ 7.70-6.58 (m, 4H), 7.49-7.30 (m, 6H), 6.79-6.71 (m,
2H), 6.61-6.55 (m, 2H), 3.75 (s, 3H), 3.74-3.42 (m, 7H), 2.80
(br s, 3H), 1.99 (m, 1H), 1.71-1.38 (m, 6H), 1.08 (s, 9H); 13C
NMR (75 MHz, CDCl3) δ 152.2, 141.9, 135.6 (2C), 135.5 (2C),
133.2, 133.0, 129.8 (2C), 127.7 (4C), 115.2 (2C), 115.0 (2C), 65.0,
62.7, 61.4, 56.3, 55.8, 41.1, 31.5, 30.1, 28.5, 26.9 (3C), 19.1; IR
(CHCl3) 3374, 2933, 2860, 1513, 1468, 1429, 1237, 1109, 1046,
822, 756, 705, 614, 506 cm-1; HRMS calcd for C31H43NO4Si (M+),
521.2961; found, 521.2965.
(2R,3S)-3-(tert-Butyldiphenylsilyloxymethyl)-1-(4-methoxy-
phenyl)-2-(3-hydroxypropyl)-pyrrolidine (16). A solution of 15
(100 mg, 0.19 mmol) and 1,1′-carbonyldiimidazole (100 mg, 0.62
mmol) in MeCN (10 mL) was refluxed for 2 h. The solvent was
evaporated in vacuo, and the residue was taken up in THF/2 N aq
NaOH, 1:1 (10 mL). This mixture was stirred for 2 h at room
temperature. The aqueous layers were extracted with Et2O (2 ×
10 mL), and the combined organic layers were dried with Na2SO4,
(R)-tert-Butyl 2-Methyl-3-oxo-3-phenylpropylcarbamate (19).
The exact conditions for the synthesis of compound 18 afforded
the title compound as a colorless oil: Rf 0.32 (25% Et2O/pentane);
[R]25D -45.4 (c 0.56, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.98-
7.91 (m, 2H), 7.58-7.51 (m, 1H), 7.48-7.41 (m, 2H), 5.03 (br s,
J. Org. Chem, Vol. 71, No. 11, 2006 4153

de Figueiredo et al.
1H), 3.82-3.69 (m, 1H), 3.37 (m, 2H), 1.38 (s, 9H), 1.17 (d, J )
7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 203.5, 156.0, 136.1,
133.2, 128.6 (2C), 128.4 (2C), 79.1, 42.8, 41.1, 28.3, 15.6; IR
(CHCl3) 3373, 2976, 2934, 1684, 1511, 1453, 1368, 1249, 1218,
1171, 972 cm-1; HRMS calcd for C15H21NO3 (M+), 207.0895;
found, 207.0896.
schungsgemeinschaft (SPP 1179 “Organokatalyse”), and Prof.
Dieter Enders for his encouragement and support.
Supporting Information Available: Copies of 1H and 13C NMR
spectra. This material is available free of charge via the Internet at
http://pubs.acs.org.
Acknowledgment. We thank the Fonds der Chemischen
Industrie for a Liebig fellowship (M.C.), the Deutsche For-
JO060130B
4154 J. Org. Chem., Vol. 71, No. 11, 2006