Regio- and stereoselective ring opening of enantiomerically enriched 2-aryl oxetanes and 2-aryl azetidines with aryl borates

Article abstract of DOI:10.1021/jo801568a

(Chemical Equation Presented) The regioselective ring opening of 2-aryl-substituted four-membered heterocyclic rings with phenols, including catechol, was achieved by the use of aryl borates in mild and neutral reaction conditions without the aid of any transition metal catalysts. While β-alkyl azetidines were found not to be reactive, optically active N-tosyl azetidines gave the corresponding β-aryloxy amines in a racemic form, thus indicating the considerable carbocationic character of the transition state. The introduction of a hydroxyl group in the azetidine ring (i.e., an azetidinol), able to anchor the aryl borate and to direct the subsequent nucleophilic delivery, was shown to determine the ring-opening process with predominant inversion of configuration. When enantiomerically enriched 2-aryl oxetanes were used, the reduced extent of racemization observed (up to 93:7 er) was rationalized by an intramolecular delivery through a six-membered transition state, giving β-aryloxy alcohols with a predominant retention of configuration (i.e., a syn-stereoselective ring opening). The aryloxy alcohols obtained, endowed with suitable functionalities, can be cyclized to give access to enantiomerically enriched 2-aryl-1,5-benzodioxepins.

Full text of DOI:10.1021/jo801568a

Regio- and Stereoselective Ring Opening of Enantiomerically
Enriched 2-Aryl Oxetanes and 2-Aryl Azetidines with Aryl Borates
Ferruccio Bertolini, Stefano Crotti, Valeria Di Bussolo, Franco Macchia, and
Mauro Pineschi*
Dipartimento di Chimica Bioorganica e Biofarmacia, UniVersita` di Pisa, Via Bonanno 33,
56126 Pisa, Italy
pineschi@farm.unipi.it
ReceiVed July 16, 2008
The regioselective ring opening of 2-aryl-substituted four-membered heterocyclic rings with phenols,
including catechol, was achieved by the use of aryl borates in mild and neutral reaction conditions without
the aid of any transition metal catalysts. While N-alkyl azetidines were found not to be reactive, optically
active N-tosyl azetidines gave the corresponding ꢀ-aryloxy amines in a racemic form, thus indicating the
considerable carbocationic character of the transition state. The introduction of a hydroxyl group in the
azetidine ring (i.e., an azetidinol), able to anchor the aryl borate and to direct the subsequent nucleophilic
delivery, was shown to determine the ring-opening process with predominant inversion of configuration.
When enantiomerically enriched 2-aryl oxetanes were used, the reduced extent of racemization observed
(up to 93:7 er) was rationalized by an intramolecular delivery through a six-membered transition state,
giving ꢀ-aryloxy alcohols with a predominant retention of configuration (i.e., a syn-stereoselective ring
opening). The aryloxy alcohols obtained, endowed with suitable functionalities, can be cyclized to give
access to enantiomerically enriched 2-aryl-1,5-benzodioxepins.
Introduction
merically pure 2-aryl-3,3-dimethyloxetanes with water and
alcohols has been described by Kellogg and co-workers.3 More
recently, a ring opening of substituted enantiomerically enriched
tertiary oxetanes with hydrogen peroxide and alkyl hydroper-
oxides catalyzed by Lewis acids, proceeding with moderate and
sometimes capricious stereoselection, has been reported.4 To
the best of our knowledge, the ring opening of oxetanes with
phenols to give 3-aryloxy alcohols has not yet been reported.
The ring opening of small-ring heterocycles with nucleophiles
is a very important topic with a large variety of applications in
synthetic organic chemistry. Most of this chemistry concerns
the use of epoxides and aziridines,1 whereas the use of their
higher homologues, oxetanes and azetidines, is under-exploited
despite their potential broad versatility as building blocks in
organic synthesis. For example, oxetanes have a large variety
of applications, but mainly in the field of polymers and in
material science.2 As regards the use of oxygen nucleophiles,
the acid-catalyzed anti-stereoselective ring opening of enantio-
(2) For recent examples, see: (a) Bouchekif, H.; Philbin, M. I.; Colclough,
E.; Amass, A. J. Macromolecules 2008, 41, 1989. (b) Crivello, J. V. J. Polym.
Sci., Part A: Polym. Chem. 2007, 45, 4331. (c) Runzinger, S. J.; Kurt, P.;
Brunson, K. M.; Wood, L.; Ohman, D. E.; Wynne, K. J. Polymer 2007, 48,
4653. (d) Kudo, H.; Nishikubo, T. J. Polym. Sci., Part A: Polym. Chem. 2007,
45, 709.
(3) Xianming, H.; Kellogg, R. M. Tetrahedron: Asymmetry 1995, 6, 1399.
(4) Dussault, P. H.; Trullinger, T. K.; Noor-e-Ain, F. Org. Lett. 2002, 4,
4591.
(1) For recent reviews, see: (a) Aziridines and Epoxides in Organic Synthesis;
Yudin, A. K., Ed.; Wiley-VCH: Weinheim, 2006. (b) Schneider, C. Synthesis
2006, 3919. (c) Sweeney, J. B. Chem. Soc. ReV. 2002, 31, 247. (d) Hu, X. E.
Tetrahedron 2004, 60, 2701. (e) Pineschi, M. Eur. J. Org. Chem. 2006, 4979.
8998 J. Org. Chem. 2008, 73, 8998–9007
10.1021/jo801568a CCC: $40.75 2008 American Chemical Society
Published on Web 10/22/2008

Ring Opening of 2-Aryl Oxetanes and Azetidines
SCHEME 1. Different Reactivity of 2-Phenyloxetane and 1-Phenyloxirane with Borate 2a
This may probably be ascribed to the absence of reactivity of
oxetanes in an SN2-type displacement with the corresponding
phenoxide in basic conditions, which is dramatically different
from that of epoxides.5 Likewise, the ring opening of azetidines
with phenols in basic conditions is very difficult to obtain, and
even the use of an in situ generated azetidinium ion occurred
after very long reaction times in drastic reaction conditions with
low yields and partial racemization.6 The synthesis of 1,3-amino
ethers by a Lewis acid catalyzed ring opening of 2-aryl-N-
tosylazetidines with alcohols and phenols has only very recently
been reported.7 However, either the ring opening afforded a
mixture of regioisomeric products with a poor yield with
phenols,7a or the stereoselectivity has not been examined.7b
Recently, we found that aryl borates behave as actiVating
nucleophiles and readily transfer the phenol moiety to aryl
epoxides and aziridines in a stereoselective fashion, without the
need for a transition metal catalyst.8 Depending on the nature
of the aryl borate, a competitive Friedel-Crafts-type alkylation
represented a very important side reaction, which became
exclusive when particularly electron-rich aryl borates were
used.9 Therefore, we envisioned that the reaction of the
homologues 2-aryl oxetanes and 2-aryl azetidines with phenols
might provide additional information about the reaction mech-
anism and a new entry to 3-phenyl-3-aryloxy alcohols and
3-phenyl-3-aryloxy amines, respectively, which are synthetically
important chiral intermediates for the synthesis of compounds
of pharmaceutical interest, widely used for the treatment of
anxiety and depression.10 Alternative simple methods for the
synthesis of these compounds in enantiomerically pure form
are based on regioselective reduction of optically active 2,3-
epoxycinnamyl alcohols,11 catalytic asymmetric or biological
reduction of 3-keto-carboxylates,12 or asymmetric hydrosilyla-
tion of 3-hydroxy-propiophenone.13 Enzymatic resolutions of
racemic 1-phenyl-3-buten-1-ol, followed by ozonolysis of the
terminal double bond have also been described.14 All these
methods comprise inter alia a Mitsunobu-etherification of the
benzylic secondary alcohol for the installation of the phenol
moiety.11-14 Other straightforward strategies are based on metal-
catalyzed stereoselective allylic etherification of cinnamyl
derivatives followed by oxidative hydroboration of the terminal
double bond.15
Here, we report our study on the development of a simple,
practical regioselective procedure for the ring opening of
enantioenriched 2-aryloxetanes and 2-arylazetidines with phe-
nols, with a particular emphasis on the stereochemical outcome
of the reaction.
Results and Discussion
As a preliminary experiment, the reaction of (R)-1-pheny-
loxetane (1a),16 readily available by basic cyclization of (R)-
3-chloro-1-phenylpropanol, with tris(3,5-dimethoxyphenyl)bo-
rate (2a) was examined. The reaction occurred at completion
in CH2Cl2 at -78 °C in 2 h (Scheme 1). Hydroxy phenol 4aa,
a Friedel-Crafts-type C-alkylation product, turned out to be
(11) (a) Gao, Y.; Sharpless, K. B. J. Org. Chem. 1988, 53, 4081. (b) Cui,
Y.-M.; Huang, Q.-Q.; Xu, J.; Chen, L.-L.; Li, J.-Y.; Ye, Q.-Z.; Li, J.; Nan, F.-J.
Biorg. Med. Chem. Lett. 2005, 15, 4130.
(12) Chemical: (a) Noyori, R.; Ohkuma, T.; Kitamura, M.; Takaya, H.; Sayo,
N.; Kumobayashi, H.; Akutagawa, S. J. Am. Chem. Soc. 1987, 109, 5856. (b)
Sterk, D.; Stephan, M. S.; Mohar, B. Tetrahedron: Asymmetry 2002, 13, 2605.
(c) Ireland, T.; Grossheimann, G.; Wieser, J. C.; Knochel, P. Angew. Chem.,
Int. Ed. 1999, 38, 3212. (d) Wu, J.; Chen, H.; Kwok, W. H.; Lam, K. H.; Zhou,
Z. Y.; Yeung, C. H.; Chan, A. S. C. Tetrahedron Lett. 2002, 43, 1539. (e) Hilborn,
J. W.; Lu, Z. H.; Jurgens, A. R.; Fang, K. Q.; Byers, P.; Wald, S. A.; Senanayake,
C. H. Tetrahedron Lett. 2001, 42, 8919Enzymatic: (f) Xu, C.; Yuan, C.
Tetrahedron 2005, 61, 2169. (g) Boaz, N. W. J. Org. Chem. 1992, 57, 4289. (h)
Schneider, M. P.; Goergens, U. Tetrahedron: Asymmetry 1992, 3, 525. (i) Liu,
H. L.; Hoff, B. H.; Anthonsen, T. J. Chem. Soc., Perkin Trans. 1 2000, 1767.
(j) Kamal, A.; Ramesh, K. G. B.; Ramu, R. Tetrahedron: Asymmetry 2002, 13,
2039. (k) Kumar, A.; Ner, D. H.; Dike, S. Y. Tetrahedron Lett. 1991, 32, 1901.
(l) Chenevert, R.; Fortier, G.; Rhlid, R. B. Tetrahedron 1992, 48, 6769.
(13) Yun, J.; Buchwald, S. L. J. Am. Chem. Soc. 1999, 121, 5640.
(14) (a) Bracher, F.; Litz, T. Biorg. Med. Chem. Lett. 1996, 4, 877. (b) Master,
H. E.; Newadkar, R. V.; Rane, R. A.; Kumar, A. Tetrahedron Lett. 1996, 37,
9253.
(5) (a) Searles, Jr. S. Heterocyclic Compounds with Three- and Four-
membered Rings; Weissberger, A., Ed; Interscience: New York, 1964; p 983.
For a recent report on a regioselective ring opening of a phenyl epoxide with a
phenoxide occurring with complete inversion of configuration at the benzylic
position, see: (b) Henegar, K. E.; Cebula, M. Org. Proc. Res. DeV. 2007, 11,
354.
(6) O’Brien, P.; Philips, D. W.; Towers, T. D. Tetrahedron Lett. 2002, 43,
7333.
(7) (a) Ghorai, M. K.; Das, K.; Shukla, D. J. Org. Chem. 2007, 72, 5859.
(b) Dwivedi, S. K.; Gandhi, S.; Rastogi, N.; Singh, V. K. Tetrahedron Lett.
2007, 48, 5375.
(8) Pineschi, M.; Bertolini, F.; Haak, R. M.; Crotti, P.; Macchia, F. Chem.
Commun. 2005, 1426.
(9) (a) Bertolini, F.; Crotti, P.; Macchia, F.; Pineschi, M. Tetrahedron Lett.
2006, 47, 61. (b) Pineschi, M.; Bertolini, F.; Crotti, P.; Macchia, F. Org. Lett.
2006, 8, 2627.
(10) Robertson, D. W.; Jones, N. D.; Swartzendruber, J. K.; Yang, K. S.;
Wong, D. T. J. Med. Chem. 1988, 31, 185.
(15) Stereospecific: (a) Trost, B. M.; Fraisse, P. L.; Ball, Z. T. Angew Chem.
Int. Ed. 2002, 41, 1059. Enantioselective: (b) Onitsuka, K.; Okuda, H.; Sasai,
H. Angew. Chem., Int. Ed. 2008, 47, 1454. and pertinent references therein.
(16) Lo, M. M. C.; Fu, G. C. Tetrahedron 2001, 57, 2621.
J. Org. Chem. Vol. 73, No. 22, 2008 8999

Bertolini et al.
TABLE 1. Ring Opening of Oxetane (R)-1a with Aryl Boratesa
the main reaction product (65% of the crude mixture), and it
was obtained with low stereoselectivity (56:44 er). This was
accompanied with a significant amount (35% of the crude
mixture) of the corresponding O-alkylated product 3aa, showing
good stereoselectivity (93:7 er). A comparison of these results
with those obtained with structurally related 2-phenyloxirane
under the same reaction condition (exclusive formation of
Friedel-Crafts-type product with a reduced extent of racemi-
zation),9a clearly indicated how phenyloxetane 1a was more
prone to the O-alkylation ring-opening process than the corre-
sponding phenyloxirane and that it was possible to obtain the
corresponding 3-aryloxy alcohol with a slight erosion of
enantiomeric enrichment.
On the other hand, the Friedel-Crafts C-alkylation seemed
to be a less favored and appealing reaction pathway for oxetanes
with respect to the same reaction carried out with styrene oxide.
Next we investigated the reaction of commercially available
triphenylborate 2b with (R)-2-phenyloxetane 1a in THF at room
temperature. This substrate afforded the desired ꢀ-aryloxy
alcohol 3ab with complete regioselectivity at the benzylic
position and good stereoselectivity (87:13 er), without the
formation of any Friedel-Crafts-type reaction products (Table
1, entry 1). The isolated yield of aryloxy alcohol 3ab was
moderate due to the formation of substantial amounts (ca. 30%)
of 1-phenyl-1,3-propanediol. In order to study the influence of
borates on the stereoselectivity of the ring-opening process,
several borates were prepared from the corresponding substituted
phenols by acid-base reaction with BH3-Me2S,17 and they were
allowed to react with oxetane 1a in THF at room temperature,
giving the corresponding 3-aryloxy alcohols. It was found that
by using dichloromethane as well as THF, the outcome of the
reaction showed only marginal variations. It should be noted
that the attack of the phenol moiety occurred with complete
regioselectivity at the benzylic position of the oxetane ring, and
only products deriving from an O-alkylation ring opening
process were found in the crude mixtures. Furthermore, a
reduced extent of racemization during the ring opening of
oxetane 1a was found with aryl borates containing electron-
withdrawing substituents in the ortho position (entries 2-4).
In particular, highly stereoselective ring opening was obtained
when tris(2-chlorophenyl)borate 2d (93:7 er) was used (entry
3).
Benzo[d][1,3,2]dioxaborol-2-ol (2f), which is a compound
readily prepared by esterification between boric acid and
catechol, proved to be an effective reagent for a mild and
unprecedented introduction of a catechol moiety into an oxetane
ring (entry 5). This is quite a remarkable result, considering
that the reaction protocol occurs under neutral conditions and
that not even the use of catechol in drastic alkaline reaction
conditions (NaH/EtOH reflux) allowed the ring opening of
oxetanes with catechol, unlike the corresponding reaction
reported for epoxides.18 The ring opening occurred smoothly
also by the use of borates bearing substituents in a different
position of the aromatic ring, giving the corresponding O-
alkylated products with complete regioselectivity, satisfactory
isolated yields, and a reduced extent of racemization (entries
6-10). Even if the reaction can be carried out with only 1.0
equiv of the aryl borate, the present use of 1.66 equiv proved
to be optimal with respect to reaction times and stereoselec-
tivities.
a All reactions were carried out in THF at room temperature in
accordance with the general procedure, unless stated otherwise.
b Isolated yields of the product after chromatographic purification (SiO2).
c Determined by HPLC analysis on CSPs. d Reaction carried out in
CH2Cl2.
As aryl oxetane 1a does not react in the reaction with the
corresponding phenoxides under basic conditions, the demon-
stration of the main stereoselective pathway of the ring opening
reported in Table 1 by a reference anti-stereoselective reaction
(17) Brown, C. A.; Krishnamurthy, S. J. Org. Chem. 1978, 43, 2731.
(18) Procopiou, P. A.; Brodie, A. C.; Deal, M. J.; Hayman, D. F.; Smith,
G. M. J. Chem. Soc., Perkin Trans. 1 1996, 2249.
9000 J. Org. Chem. Vol. 73, No. 22, 2008

Ring Opening of 2-Aryl Oxetanes and Azetidines
SCHEME 2. Absolute Configuration of ꢀ-Aryloxy Alcohols: Synthesis of (R)-Tomoxetine Hydrochloride
SCHEME 3.
Ring Opening of Oxetane (R)-1a with
in THF afforded good yield of aryloxy alcohol 3ad, but this
compound was likewise recovered in an almost racemic form
(56/44 er). The use of stoichiometric amounts of B(OBu)3 in
the presence of 2-chlorophenol gave a very sluggish reaction,
and only after 48 h was the reaction complete.20 Subsequent
HPLC analysis showed that the major enantiomer was the same
obtained by the use of the corresponding aryl borate 2d (see
entry 3, Table 1), albeit an increased racemization was observed
(71/29 er).
2-Chlorophenol in the Presence of External Lewis Acids
The fact that, in all of the reactions of oxetane 1a with aryl
borates examined, the phenol attacks exclusively at the benzylic
carbon atom seems to imply a considerable cationic character
of the transition state. As a result, the possible effect of
substituents on the aryl moiety of the oxetane on the stereose-
lective outcome of the ring-opening reaction was examined.
and subsequent HPLC analysis on chiral stationary phases was
not as simple as for epoxides.5b,8 To address this issue, we
envisioned that our reaction protocol might be used for the
synthesis of a compound of known absolute configuration, such
as tomoxetine (Scheme 2).10
For this purpose, enantiomerically enriched aryl oxetane 1b
and 1c, with an electron-withdrawing (m-Cl) and an electron-
donating group (p-Me) on the aryl moiety, respectively, were
prepared. (S)-2-(3-Chlorophenyl)oxetane 1b was obtained in
enantioenriched form from the corresponding commercially
available (R)-3-chlorostyrene oxide by means of a homologation
reaction which makes use of trimethylsulfoxonium iodide in
basic conditions (Scheme 4, eq a).21 (S)-2-p-Tolyloxetane 1c
was prepared by asymmetric reduction of 3-chloro-1-p-tolyl-
propan-1-one with (R)-CBS to give (S)-3-chloro-1-p-tolyl-
propan-1-ol 5c with good yields (76%) and a very high
enantioselectivity (ee > 98%).22 A simple cyclization under
basic conditions afforded quantitatively the corresponding
enantiomerically pure aryl oxetane 1c (Scheme 4, eq b). To our
surprise, the reaction of aryl oxetane 1b with tris(2-bromophe-
nyl)borate (2e) was complete in 1 h at room temperature and
afforded aryloxy alcohol 3be with good enantiomeric ratio
(Scheme 5). The ring opening of p-methyl-substituted oxetane
1c was even faster, and compound 3ce was obtained with a
good isolated yield but with an increased racemization. Con-
sidering that unsubstituted phenyl oxetane 1a reacted with borate
2e affording the corresponding aryloxy alcohol 3ae with an 87/
13 enantiomeric ratio (see entry 4, Table 1), this qualitatively
means that the degree of racemization is directly related to the
stability of the cationoid intermediate formed.
Thus, the ring opening of phenyloxetane 1a with tris(2-
methylphenyl)borate 2l afforded exclusively aryloxy alcohol 3al
with acceptable isolated yield (61%) and stereoselectivity (80:
20 er) (see Supporting Information for details). In accordance
with a previously described procedure,11a the subsequent me-
sylation and nucleophilic substitution with 40% aqueous MeNH2
afforded (R)-tomoxetine. The measurement of the optical
rotatory power of the obtained sample ([R]20D ) -32.3, c 1.01,
MeOH) compared with the literature data indicating that the
ring-opening reaction of oxetane 1a had occurred with a
predominant enantioretention of configuration (i.e., a syn-
stereoselective ring opening). Further confirmation of the
stereoselectivity of the ring opening came from the synthesis
of scalemic (R)-fluoxetine from ꢀ-aryloxy alcohol 3ah (Table
1, entry 7) and comparison of the corresponding optical rotatory
power.19
In order to check the validity and synthetic utility of our
protocol for the ring opening of aryl oxetanes with aryl borates,
some alternative procedures based on Lewis acids catalyzed
reactions were considered. The use of an external Lewis acid
(LA) in combination with a suitable nucleophile represents one
of the most common ways of inducing the ring opening of small-
ring heterocycles, such as epoxides and aziridines.1 The reaction
of oxetane (R)-1a with an excess of 2-chlorophenol in the
presence of catalytic amounts (10 mol %) of Cu(OTf)2 in THF,
or stoichiometric amounts of BF3-Et2O in CH2Cl2, afforded a
complex mixture of products, in which also Friedel-Crafts-
type products were found (Scheme 3 and Supporting Informa-
tion). Low yields of the O-alkylated product 3ad in an almost
racemic form (58/42 er) were obtained by the use of catalytic
amounts of Yb(OTf)3, while the reaction catalyzed by Sc(OTf)3
Once again, it should be noted the different behavior between
three- and four-membered oxygenated rings during ring opening.
In fact, in a separate experiment, the related ring opening of
3-chlorostyrene oxide with aryl borate 2e was much slower (40%
conversion in 2 days at room temperature). As these reactions
are under electronic control, this different behavior is probably
(20) Simple trialkyl borates such as B(OBu)3 and B(OMe)3 are not reactive
with oxetane 1a.
(21) Okuma, K.; Tanaka, K.; Kaji, S.; Ohta, H. J. Org. Chem. 1983, 48,
5133.
(22) Corey, E. J.; Helal, C. J. Angew. Chem., Int. Ed. 1998, 37, 1986.
(19) The major enantiomers of the other aryloxy alcohols obtained in this
study were assumed to have the same configuration as the known cases.
J. Org. Chem. Vol. 73, No. 22, 2008 9001

Bertolini et al.
SCHEME 4. Synthesis of Optically Active Substituted Aryl Oxetanes 1b and 1c
SCHEME 5. Reactions of Substituted Enantioenriched Aryl
Oxetanes 1b and 1c with Borate 1b
representative aryl borates (Table 2). As expected, the nature
of the nitrogen protecting group is very important, and strongly
basic 1-methyl 2-phenyl azetidine did not give any ring-opened
products (entry 1, Table 2). It should be noted that unlike from
the corresponding ring opening of aryl oxetanes, the ring
opening of racemic N-tosylazetidine 6a with borate 2j in THF
at room temperature did not occur at all after 18 h (data not
shown in Table 2). A simple change of the reaction solvent to
CH2Cl2 and a reaction temperature of 40 °C for the same period
gave complete conversion, and it was possible to isolate the
corresponding 3-aryloxy amine 7aj with a good yield after
chromatographic purification on silica gel (entry 2). However,
when the same reaction was carried out with enantiomerically
enriched (R)-N-tosylazetidine 6a (95:5 er), obtained by a slight
modification of the procedure of homologation that makes use
of trimethylsulfoxonium iodide in basic conditions reported by
Nadir et al.,24 a complete racemization was observed (entry 3).
Considering this stereochemical outcome, all subsequent reac-
tions with differently substituted aryl borates were carried out
with racemic azetidine 6a and gave fair to very good yields of
the corresponding ring-opened products, with complete regio-
control of the nucleophilic attack at the benzylic position (entries
4-8). The complete racemization observed would indicate that
a benzylic carbocation is formed without the occurrence in this
case of any internal delivery of the phenol moiety to preserve
stereochemistry.
due to the higher stability of the carbenium ions formed from
oxetanes, compared with that of the corresponding structures
deriving from epoxides.23
The selective formation of a C-O bond at the benzylic
position with a reduced extent of racemization found in our
protocol might be reasonably explained by admitting a prefer-
ential internal delivery of the aryloxide moiety attached to the
former oxetane oxygen by the boron tether in a six-membered
transition state, as depicted in Figure 1. First of all, the
coordination of boron to the oxygen of oxetane produces the
formation of an advanced carbocationic species, such as A
(Figure 1), which rapidly evolves to a six-membered transition
state B, which allows the internal deliVery of the nucleophile,
with retention of configuration. It is likely that the more stable
carbenium ion derived from oxetane 1c can be attacked by the
oxygen of the phenol in accordance with a SN1-type mechanism.
Clearly, a partial racemization occurring via rotation of 90°
around the C1-C2 bond after formation of the carbocationic
species from the original enantiopure oxetane, followed by an
intramolecular delivery of the aryloxide moiety (structure C),
cannot be ruled out. Accordingly, whenever external Lewis acids
have been used (see Scheme 3), an intramolecular delivery of
the aryloxide was not conceivable, and a SN1-type reaction
occurred on the intermediate carbocation, giving extensive
racemization. Furthermore, in this framework, also other reaction
paths, including Friedel-Crafts-type reactions, become possible.
Ring Opening Reactions of 2-Aryl Azetidines and 2-Aryl
Azetidinols. We also investigated the ring-opening reaction of
differently N-protected 2-aryl azetidines 6a and 6b with some
FIGURE 1. Plausible mechanism of the internal delivery of aryloxide
moiety.
In this framework, we speculated that the presence of a
hydroxyl group on the azetidine ring (i.e., an azetidinol) might
change the stereochemical outcome of the ring opening by
coordination with the aryl borate or anchimeric assis-
tance.
Although there have been several reports describing the
reactions of phenols with azetidinols at elevated temperatures
in basic conditions to prepare compounds of pharmaceutical
interest,25 the ring opening of activated azetidinols has been
minimally explored and a mild procedure is completely lack-
(23) Balsamo, A.; Crotti, P.; Ferretti, M.; Macchia, F. J. Org. Chem. 1975,
40, 2870.
(24) Nadir, U. K.; Sharma, R. S.; Koul, V. K. J. Chem. Soc., Perkin Trans.
1 1991, 2015.
9002 J. Org. Chem. Vol. 73, No. 22, 2008

Ring Opening of 2-Aryl Oxetanes and Azetidines
TABLE 2. Ring Opening of Azetidines 6a and 6b with Aryl Boratesa
SCHEME 6. Ring Opening of Differently Protected
Azetidinols with Borate 2j
SCHEME 7. Stereoselective Synthesis of (2S*,3R*)-Aryloxy
Amino Alcohol 9
pure form with a satisfactory 62% yield after chromatographic
purification. It was significant that the corresponding azetidinol
6e, bearing a highly hindered t-butyldimethylsilyl protecting
group, was completely unreactive after 4 days at 40 °C.
As it was not possible to ascertain unequivocally the relative
configuration of the ring-opened product 8dj by NMR analysis,
an independent synthesis of the corresponding diastereoisomer
9, in principle obtainable from the reaction, was undertaken
(Scheme 7). Thus, in accordance with a previously described
procedure,29 the regioselective ring opening of phenyl glycidol
with sodium 3-chlorophenoxide supported by ꢀ-cyclodextrin in
a All reactions were carried out in CH2Cl2 at 40 °C for 24 h.
b Isolated yields of the product after chromatographic purification (SiO2).
ing.26 We prepared 2-phenyl azetidinols 6c, 6d, and 6e following
reported methods27,28 and allowed them to react with aryl borate
2j. Coherently with the results obtained with azetidine 6b (Table
2), 1-cyclohexyl 2-phenyl azetidinol 6c gave no ring opening
after 24 h at 40 °C. On the other hand, the corresponding
reaction of (2R*,3S*)-N-tosyl-protected azetidinol 6d with borate
2j occurred at completion and gave a 92:8 mixture of aryloxy
amino alcohols 8dj and 9, respectively. It was possible to isolate
(2S*, 3S*)-3-aryloxy amino alcohol 8dj in diastereoisomerically
(25) (a) Julia Arechaga, G.; Vila Casas, A. Spanish Patent ES 541017, 1985.
(b) Vedrilla Veit, D. Spanish Patent ES 459725, 1978. (c) Tucker, H. British
Patent GB 1456525, 1976. (d) Koeppe, H.; Kummer, W.; Staehle, H. German
Patent DE 2503222, 1976. (e) Imperial Chemical Industries Ltd., U.K. Jpn. Kokai
Tokkyo Koho JP 50032135, 1975. (f) Laboratorio Martin Cuatrecasas, Spanish
Patent ES 438367, 1976. (g) Tsukamoto, K.; Suzuki, Y. Jpn. Tokkyo Koho JP
47019259, 1972. (h) Tsukamoto, K.; Suzuki, Y.; Izuni, A.; Hiramatsu, Y. German
Patent DE 2058532, 1972. (i) Tsukamoto, K.; Suzuki, Y.; Izuni, A.; Hiramatsu,
Y. Jpn. Tokkyo Koho JP 46028534, 1971.
(26) Higgins, R. H.; Faircloth, W. J.; Baughman, R. G.; Eaton, Q. L. J. Org.
Chem. 1994, 59, 2172. and pertinent references therein.
J. Org. Chem. Vol. 73, No. 22, 2008 9003

Bertolini et al.
SCHEME 8. Possible Routes to Enantiomerically Enriched
2-Phenyl-1,5-benzodioxepin (11)
to give the same compound 11 with a reduced overall yield
and a slight increase in the enantiomeric enrichment.
Conclusions
To sum up, we report that readily available aryl borates
behave as activating nucleophiles and react with 2-aryl oxetanes
and N-sulfonyl 2-aryl azetidines to give the corresponding
synthetically useful ꢀ-aryloxy alcohols and ꢀ-aryloxy amines,
respectively, with fair to good yields. The reactions occur
regioselectively in mild and neutral reaction conditions and
nicely complement the known methods for the ring opening of
these somewhat disregarded heterocyclic systems with respect
to epoxides and aziridines. In particular, we have shown that
the reactions of enantiomerically enriched 2-aryl oxetanes with
aryl borates proceed with a predominant retention of configu-
ration (up to 93:7 er), whereas the ring opening in alkaline
conditions did not occur at all, and the use of Lewis acid
catalyzed protocols afforded a mixture of products and/or
extensive racemization. When reactive functionalities are present
in the ꢀ-aryloxy alcohol, intramolecular cyclization allows a
new access to 2-aryl-1,5-benzodioxepins in an enantioenriched
form.
H2O at 50 °C for 20 h afforded aryloxy diol 10 with 75% yield.
Subsequent monotosylation of the primary hydroxy functionality
and its nucleophilic substitution with p-toluenesulfonamide
sodium salt in anhydrous DMF at 100 °C for 16 h afforded
compound 9 (25% yield for two steps; see Supporting Informa-
tion for details).
The involvement of the hydroxy functionality in anchimeric
assistance during the ring opening of azetidine 6d would have
led to retention of configuration, affording the opposite dias-
tereoisomer, (i.e., (2S*,3R*)-aryloxy amino alcohol 9). Hence,
the predominant inversion of configuration of the ring opening
found in the reaction of azetidinol 6d points to a boron atom
engaged in the formation of an ate-complex with the free
secondary hydroxyl group. In this way the phenol moiety is
stereoselectively delivered at the benzylic position in a SN2
fashion with inversion of configuration. The fact that this
reaction manifold is not possible when the hydroxyl group is
protected or when basic azetidinol 6c is used, supports this
notion.
Synthesis of 2-Phenyl-1,5-benzodioxepin. As some of the
new aryloxy alcohols prepared (see Table 1) from the ring-
opening reactions of oxetanes possess reactive functional
groups that can undergo substitution reactions, we envisioned
that these compounds might be valuable intermediates for
the obtainment of 2-aryl-1,5-benzodioxepins.30 In particular,
the Mitsunobu-cyclodehydration of compound 3af deriving
from the ring opening of the optically active oxetane 1a with
benzo[d][1,3,2]dioxaborol-2-ol (2f) (Table 1, entry 5), af-
forded 1,5-benzodioxepin 11 with a satisfactory overall yield
(72%) and with no loss of optical purity (72:28 er) compared
with the ring-opened product 3af (Scheme 8).31 Alternatively,
it is possible to use o-bromophenyloxy alcohol 3ae (87:13
er) in an intramolecular Pd-catalyzed substitution reaction,32
Experimental Section
Aryl borates 2a-l were prepared following a previously de-
scribed procedure17 and were used immediately after their preparation.
General Procedure for the Ring Opening of Oxetanes (Table
1). A solution of aryl borate (0.5 mmol) in THF (1.0 mL) was added
to a stirred solution of the oxetane (0.3 mmol) in THF (0.5 mL)
under argon. The reaction was followed by TLC after complete
consumption of the starting oxetane. After evaporation of the
solvent, the crude reaction mixture was then purified by silica gel
column chromatography, to give the pure compounds of type 3.
(R)-3-Phenoxy-3-phenylpropan-1-ol (3ab). (Entry 1, Table 1)
Using the general procedure triphenylborate (2b) (145.0 mg, 0.5
mmol) in THF (1.0 mL) was added at room temperature to a
solution of (R)-2-phenyl oxetane (1a) (40.2 mg, 0.3 mmol) in THF
(0.5 mL). After 3.0 h at room temperature, the crude mixture was
purified by column chromatography eluting with hexanes/AcOEt
8:2 to give compound 3ab (34.2 mg, 50%) as an oil. [R]20D ) +20.0
1
(c 2.0, CHCl3, 87:13 er). H NMR (250 MHz, CDCl3) δ 1.96 (br,
s, 1H, OH); 2.00-2.28 (m, 2H); 3.75-3.89 (m, 2H); 5.36 (dd, 1H,
J1 ) 8.8 Hz, J2 ) 4.3 Hz); 6.80-6.90 (m, 3H); 7.13-7.40 (m,
7H). 13C NMR (62.5 MHz, CDCl3) δ 41.2, 59.9, 78.1, 115.9, 121.0,
125.8, 127.6, 128.7, 129.4, 1415, 157.8. Anal. Calcd for C15H16O2:
C, 78.92; H, 7.06. Found: C, 78.56; H, 7.08. Enantiomeric ratio
determined by chiral HPLC (Chiralcel OD-H), flow rate: 0.5 mL/
min, mobile phase: hexane/isopropanol 90/10, retention times (min):
16.7 (S, minor stereoisomer), 19.0 (R, major stereoisomer).
(R)-3-(2-Fluorophenoxy)-3-phenylpropan-1-ol (3ac). (Entry 2,
Table 1) Using the general procedure, tris(2-fluorophenyl)borate
(2c) (177.0 mg, 0.5 mmol) in THF (1.0 mL) was added at room
temperature to a solution of (R)-2-phenyl oxetane (1a) (40.2 mg,
0.3 mmol) in THF (0.5 mL). After 1 h at room temperature, the
crude mixture was purified by column chromatography eluting with
hexanes/AcOEt 8:2 to give compound 3ac (57.6 mg, 78%) as an
oil. [R]20D ) +72.5 (c 0.2, CHCl3, 88:12 er). 1H NMR (250 MHz,
CDCl3) δ 2.04-2.14 (m, 2H); 2.24-2.30 (m, 1H); 3.73-3.98 (m,
2H); 5.35 (dd, 1H, J1 ) 8.8 Hz, J2 ) 4.3 Hz); 6,74-6.86 (m, 3H);
6.98-7.07 (m, 1H); 7.22-7.39 (m, 5H). 13C NMR (62.5 MHz,
(27) For azetidinol 6c, see: Okutani, T.; Morimoto, A.; Kaneko, T.; Masuda,
K. Chem. Pharm. Bull. Jpn. 1974, 22, 1490.
(28) For azetidinols 6d and 6e, see: Matsuura, F.; Hamada, Y.; Shiori, T.
Tetrahedron 1994, 50, 265.
(31) For the recent use of Mitsunobu cyclodehydration for the synthesis of
2,3-dihydrobenzofurans, see: Bertolini, F.; Crotti, P.; Di Bussolo, V.; Macchia,
F.; Pineschi, M. J. Org. Chem. 2007, 72, 7761, and references therein.
(32) Kuwabe, S.; Torraca, K. E.; Buchwald, S. L. J. Am. Chem. Soc. 2000,
122, 12907.
(29) Narender, M.; Reddy, M. S.; Nageswar, Y. V. D.; Rama Rao., K. HelV.
Chim. Acta 2007, 90, 1107.
(30) Ganesh, T.; Krupadanam, G. L. Indian J. Chem., Sect. B 1998, 37B
(1), 34.
9004 J. Org. Chem. Vol. 73, No. 22, 2008

Ring Opening of 2-Aryl Oxetanes and Azetidines
CDCl3) δ 41.0, 60.0, 80.2, 116.0, 116.3, 117.2, 117.3, 121.5, 121.6,
124.1 (2 C); 125.9, 127.9, 128.7, 140.9, 151.2. Anal. Calcd for
C15H15FO2: C, 73.15; H, 6.14. Found: C, 73.22; H, 6.21. Enantio-
meric ratio determined by chiral HPLC (Chiralcel OD-H), flow rate:
0.5 mL/min, mobile phase: hexane/isopropanol 92/8, retention times
(min): 19.4 (R, major stereoisomer), 22.3 (S, minor stereoisomer).
(R)-3-(2-Chlorophenoxy)-3-phenylpropan-1-ol (3ad). (Entry 3,
Table 1) Using the general procedure, tris(2-chlorophenyl)borate
(2d) (196.0 mg, 0.5 mmol) in THF (1.0 mL) was added at room
temperature to a solution of (R)-2-phenyl oxetane (1a) (40.2 mg,
0.3 mmol) in THF (0.5 mL). After 1 h at room temperature the
crude mixture was purified by column chromatography eluting with
hexanes/AcOEt 8:2 to give compound 3ad (65.3 mg, 83%) as an
oil. 1H NMR (250 MHz, CDCl3) δ 2.08-2.33 (m, 2H); 2.42 (br, s,
1H, OH); 3.75- 3.91 (m, 2H); 5.41 (dd, 1H, J1 ) 8.0 Hz, J2 ) 4.3
Hz); 6.68 (d, 1H, J ) 8.3 Hz); 6.76-6.83 (m, 1H); 6.95-7.02 (m,
1H); 7.22-7.31 (m, 5H). 13C NMR (62.5 MHz, CDCl3) δ 41.1,
59.8, 79.8, 115.2, 121.6, 125.7, 127.5, 127.9, 128.8, 130.1, 140.7,
153.1, 153.4. Anal. Calcd for C15H15ClO2: C, 68.57; H, 5.75. Found:
C, 68.34; H, 5.65. Enantiomeric ratio determined by chiral HPLC
(Chiralcel OD-H), flow rate: 0.5 mL/min, mobile phase: hexane/
isopropanol 94/6, retention times (min): 26.3 (S, minor stereoiso-
mer), 27.3 (R, major stereoisomer).
(R)-3-(2-Bromophenoxy)-3-phenylpropan-1-ol (3ae). (Entry 4,
Table 1) Using the general procedure, tris(2-bromophenyl)borate
(2e) (261.9 mg, 0.5 mmol) in THF (1.0 mL) was added at room
temperature to a solution of (R)-2-phenyl oxetane (1a) (40.2 mg,
0.3 mmol) in THF (0.5 mL). After 1 h at room temperature the
crude mixture was purified by column chromatography eluting with
hexanes/AcOEt 8:2 to give compound 3ae (53.2 mg, 58%) as an
oil. 1H NMR (250 MHz, CDCl3) δ δ 2.10-2.42 (m, 2H); 3.73-3.94
(m, 2H); 5.43 (dd, 1H, J1 ) 8.0 Hz, J2 ) 4.5 Hz); 6.66 (d, 1H, J
) 7.9 Hz); 6.68-6.80 (m, 1H); 6.91-7.39 (m, 6H); 7.49 (dd, 1H,
J1 ) 8.0 Hz, J2 ) 1.4 Hz). 13C NMR (62.5 MHz, CDCl3) δ 41.1,
59.8, 79.7, 114.9, 122.0, 125.7, 127.8, 128.1, 128.2, 128.8, 132.2,
140.6, 153.4. Anal. Calcd for C15H15BrO2: C, 58.65; H, 4.92. Found:
C, 58.44; H, 4.86. Enantiomeric ratio determined by chiral HPLC
(Chiralcel OD-H), flow rate: 0.5 mL/min, mobile phase: hexane/
isopropanol 90/10, retention times (min): 18.3 (S, minor stereo-
isomer), 21.3 (R, major stereoisomer).
60.1, 79.3, 114.5, 117.1, 125.9, 127.6, 128.6, 141.6, 151.9, 153.9.
Anal. Calcd for C16H18O3: C, 74.39; H, 7.02. Found: C, 73.93; H,
6.94. Enantiomeric ratio determined by chiral HPLC (Chiralcel OD-
H), flow rate: 0.5 mL/min, mobile phase: hexane/isopropanol 90/
10, retention times (min): 19.5 (R, major stereoisomer), 22.3 (S,
minor stereoisomer).
(R)-3-Phenyl-3-(4-(trifluoromethyl)phenoxy)propan-1-ol (3ah).
(Entry 7, Table 1) Using the general procedure, tris(p-(trifluorom-
ethyl)phenyl)borate (2h) (247.0 mg, 0.5 mmol) in THF (1.0 mL)
was added at room temperature to a solution of (R)-(1a) (40.2 mg,
0.3 mmol) in THF (0.5 mL). After 1 h at room temperature, the
mixture was purified by column chromatography eluting with
hexanes/AcOEt 8:2 to give compound 3ah (71.9 mg, 81%) as an
oil. 1H NMR (250 MHz, CDCl3) δ 1.77 (br, s, 1H, OH); 2.00-2.14
(m, 1H); 2.20-2.31 (m, 1H); 3.70-3.92 (m 2H); 5.41 (dd, 1H, J1
) 8.5 Hz, J2 ) 4.5 Hz); 6.90 (d, 2H, J ) 8.5 Hz); 7.20-7.35 (m,
5H); 7.41 (d, 2H, J ) 8.5 Hz). 13C NMR (62.5 MHz, CDCl3) δ
41.1, 59.4, 77.8, 115.7, 125.7, 126.7 (2 C), 126.8, 126.9, 127.9,
128.8, 140.7. Anal. Calcd for C15H15NO4: C, 65.92; N, 5.13; H,
5.53. Found: C, 65.96; N, 5.08; H, 5.42. Enantiomeric ratio
determined by chiral HPLC (Chiralcel OD-H), flow rate: 0.5 mL/
min, mobile phase: hexane/isopropanol 90/10, retention times (min):
14.4 (R, major stereoisomer), 15.9 (S, minor stereoisomer).
(R)-3-(4-Nitrophenoxy)-3-phenylpropan-1-ol (3ai). (Entry 8,
Table 1) Using the general procedure, tris(p-nitrophenyl)borate (2i)
(212.5 mg, 0.5 mmol) in CH2Cl2 (1.0 mL) was added at room
temperature to a solution of (R)-1a (40.2 mg, 0.3 mmol) in CH2Cl2
(0.5 mL). After 1 h at room temperature the mixture was purified
by column chromatography eluting with hexanes/AcOEt 7:3 to give
1
compound 3ai (47.6 mg, 58%) as an oil. H NMR (250 MHz,
CDCl3) δ 1.99-2.16 (m, 1H); 2.20-2.34 (m 1H); 2.30-2.60 (br,
1H, OH); 3.68-3.92 (m, 2H); 5.47 (dd, 1H, J1 ) 8.0 Hz, J2 ) 5.0
Hz); 6.88 (d, 2H, J ) 9.0 Hz); 7.22-7.34 (m, 5H); 8.02 (d, 2H, J
) 9.0 Hz). 13C NMR (62.5 MHz, CDCl3) δ 41.0, 58.9, 78.1, 115.6,
115.8, 125.7, 128.2, 129.0, 140.1, 163.1. Anal. Calcd for
C16H15F3O2: C, 64.86; H, 5.10. Found: C, 64.97; H, 5.02. Enan-
tiomeric ratio determined by chiral HPLC (Chiralcel OD-H), flow
rate: 0.5 mL/min, mobile phase: hexane/isopropanol 90/10, retention
times (min): 33.4 (R, major stereoisomer), 35.6 (S, minor stereo-
isomer).
(R)-3-(3-Chlorophenoxy)-3-phenylpropan-1-ol (3aj). (Entry 9,
Table 1) Using the general procedure described above, a solution
of tris(3-chlorophenyl)borate (2j) (196.0 mg, 0.5 mmol) in THF
(1.0 mL) was added at room temperature to a solution of (R)-(1a)
(40.2 mg, 0.3 mmol) in THF (0.5 mL). The mixture was allowed
to react for 1 h at room temperature. The mixture was purified by
column chromatography eluting with hexanes/AcOEt 8:2 to give
(R)-2-(3-Hydroxy-1-phenylpropoxy)phenol (3af). (Entry 5, Table
1) Using the general procedure, benzo[d][1,3,2]dioxaborol-2-ol (2f)
(68.0 mg, 0.5 mmol) in THF (1.0 mL) was added at room
temperature to a solution of (R)-2-phenyl oxetane (1a) (40.2 mg,
0.3 mmol) in THF (0.5 mL). After 2 h at room temperature the
crude mixture was purified by column chromatography eluting with
hexanes/AcOEt 7:3 to give compound 3af (63.0 mg, 86%) as a
solid. Mp ) 92-93 °C. 1H NMR (250 MHz, CDCl3) δ 2.00-2.11
(m, 1H); 2.22-2.34 (m, 2H); 3.80-3.89 (m 1H); 3.95-4.03 (m,
1H); 5.19 (dd, 1H, J1 ) 9.0 Hz, J2 ) 3.8 Hz); 6.58-6.61 (m, 2H);
6.78-6.85 (m, 1H); 6.90 (d, 1H, J ) 7.3 Hz); 7.03 (br s, 1H, OH);
7.25-7.36 (m, 5H). 13C NMR (62.5 MHz, CDCl3) δ 40.4, 60.2,
81.3, 115.4, 116.8, 119.8, 122.8, 126.1, 128.0, 128.7, 141.3, 145.4,
147.3. Anal. Calcd for C15H16O3: C, 73.75; H, 6.60. Found: C,
73.63; H, 6.71. Enantiomeric ratio determined by chiral HPLC
(Chiralcel OD-H), flow rate: 0.5 mL/min, mobile phase: hexane/
isopropanol 90/10, retention times (min): 22.1 (S, minor stereo-
isomer), 28.0 (R, major stereoisomer).
(R)-3-(4-Methoxyphenoxy)-3-phenylpropan-1-ol (3ag). (Entry 6,
Table 1) Using the general procedure, tris(p-methoxyphenyl)borate
(190.0 mg, 0.5 mmol) in THF (1.0 mL) was added at room
temperature to a solution of (R)-1a (40.2 mg, 0.3 mmol) in THF
(0.5 mL). After 2.0 h at room temperature, the crude mixture was
purified by column chromatography eluting with hexanes/AcOEt
8:2 to give compound 3ag (40.3 mg, 52%) as an oil. [R]20D ) +26.7
(c 1.7, CHCl3). 1H NMR (250 MHz, CDCl3) δ 2.00-2.22 (m, 3H);
3.68 (s, 3H); 3.69-3.81 (m, 2H); 5.25 (dd, 1H, J1 ) 8.0 Hz, J2 )
5.0 Hz); 6.70 (d, 2H, J ) 9.0 Hz); 6.76 (d, 2H, J ) 9.0 Hz);
7.16-7.35 (m, 5H). 13C NMR (62.5 MHz, CDCl3) δ 41.1, 55.6,
1
compound 3aj (62.1 mg, 79%) as an oil. H NMR (250 MHz,
CDCl3) δ 1.90-2.31 (m, 3H); 3.70-3.92 (m, 2H); 5.34 (dd, 1H,
J1 ) 8.5 Hz, J2 ) 3.8 Hz); 6.71 (d, 1H, J ) 8.0 Hz); 6.80-6.89
(m, 2H); 7.03-7.12 (m, 1H); 7.20-7.42 (m, 5H). 13C NMR (62.5
MHz, CDCl3) δ 41.1, 59.5, 78.1, 114.1, 116.6, 121.2, 125.8, 127.9,
128.8, 130.1, 134.5, 140.9, 158.6. Anal. Calcd for C15H15ClO2: C,
68.57; H, 5.75. Found: C, 68.34; H, 5.62. Enantiomeric ratio
determined by chiral HPLC (Chiralcel OD-H), flow rate: 0.5 mL/
min, mobile phase: hexane/isopropanol 90/10, retention times (min).
20.0 (S, minor stereoisomer), 22.8 (R, major stereoisomer).
(R)-Methyl 4-(3-hydroxy-1-phenylpropoxy)-3-iodobenzoate (3ak).
(Entry 10, Table 1) Using the general procedure, borate 2k (420.6
mg, 0.5 mmol) in THF (1.0 mL) was added at room temperature
to a solution of (R)-(1a) (40.2 mg, 0.3 mmol) in THF (0.5 mL).
After 1 h at room temperature, the mixture was purified by column
chromatography eluting with hexanes/AcOEt 8:2 to give compound
1
3ak (83.8 mg, 68%) as a semisolid. H NMR (250 MHz, CDCl3)
δ 2.03-2.39 (m, 3H); 3.73-3.85 (m, 1H); 3.81 (s, 3H); 3.88-4.00
(m, 1H); 5.50 (dd, 1H, J1 ) 8.5 Hz, J2 ) 4.3 Hz); 6.60 (d, 1H, J
) 8.8 Hz); 7.12-7.35 (m, 5H); 7.75 (dd, 1H, J1 ) 8.5 Hz, J2 )
1.8 Hz); 8.40 (d, 1H, J ) 1.8 Hz). 13C NMR (62.5 MHz, CDCl3)
δ 41.1, 52.1, 59.3, 79.3, 86.3, 112.8, 124.1, 125.7, 128.1, 128.9,
J. Org. Chem. Vol. 73, No. 22, 2008 9005

Bertolini et al.
131.2, 139.9, 140.8, 159.8, 165.4. Anal. Calcd for C17H17IO4: C,
49.53; H, 4.16. Found: C, 49.88; H, 4.19. Enantiomeric ratio
determined by chiral HPLC (Chiralcel OD-H), flow rate: 0.5 mL/
min, mobile phase: hexane/isopropanol 90/10, retention times (min):
18.5 (S, minor stereoisomer), 21.1 (R, major stereoisomer).
(S)-3-(2-Bromophenoxy)-3-(3-chlorophenyl)propan-1-ol (3be).
(Scheme 5) Using the general procedure, tris(2-bromophenyl)borate
(2e) (237.1 mg, 0.45 mmol) in THF (1.0 mL) was added at room
temperature to a solution of (S)-2-(3-chlorophenyl)oxetane (1b)
(50.5 mg, 0.3 mmol) in THF (0.5 mL). After 1.5 h at room
temperature, the mixture was purified by column chromatography
3-Phenyl-3-(4-nitrophenoxy)-N-(4-methylphenyl sulfonyl)-pro-
panamine (7ai). (Entry 4, Table 2) Using the general procedure,
tris(4-nitrophenyl)borate (2i) (212.5 mg, 0.5 mmol) in CH2Cl2 (1.0
mL) was added at room temperature to a solution of 6a (86.1 mg,
0.3 mmol) in CH2Cl2 (0.5 mL). The mixture was allowed to react
for 24 h at 40 °C and purified by column chromatography eluting
with hexanes/AcOEt 8:2 to give compound 7ai (71.6 mg, 56%) as
1
a yellow oil. H NMR (250 MHz, CDCl3) δ 1.90-2.22 (m, 2H);
2.37 (s, 3H); 2.98-3.23 (m, 2H); 5.10-5.18 (m, 1H, NH);
5.26-5.35 (m, 1H); 6.79 (d, 2H, J ) 8.0 Hz); 7.12-7.32 (m, 7H);
7.69 (d, 2H, J ) 8.2 Hz); 7.99 (d, 2H, J ) 8.0 Hz). 13C NMR
(62.5 MHz, CDCl3) δ 21.5, 38.2, 39.6, 77.9, 115.7, 125.6, 125.7,
127.0, 128.3, 129.0, 129.8, 136.5, 139.4, 141.5, 143.7, 162.6. Anal.
Calcd for C22H22N2O2S: C, 61.96; N, 6.57; H, 5.20. Found: C,
61.62; N, 6.68; H, 5.18.
eluting with hexanes/AcOEt 8:2 to give compound 3be (51.2 mg,
1
50%) as an oil. [R]20 ) +34.2 (c 2.16, CHCl3). H NMR (250
D
MHz, CDCl3) δ 2.08-2.38 (m, 3H); 3.70-3.95 (m, 2H); 5.38 (dd,
1H, J1 ) 8.3, Hz, J2 ) 4.3 Hz); 6.63 (dd, 1H, J1 ) 8.5 Hz, J2 )
1.0 Hz); 6.73-6.80 (m, 1H); 7.02-7.10 (m, 1H); 7.18-7.38 (m,
4H); 7.51 (dd, 1H, J1 ) 7.8 Hz, J2 ) 1.5 Hz). 13C NMR (62.5
MHz, CDCl3) δ 41.0, 59.5, 78.8, 114.8, 122.3, 123.9, 125.9, 128.1,
128.3, 130.2, 133.4, 143.0, 153.4. Anal. Calcd for C15H14BrClO2:
C, 52.74; H, 4.13. Found: C, 52.90; H, 4.15. Enantiomeric ratio
determined by chiral HPLC (Chiralcel OD-H), flow rate: 0.5 mL/
min, mobile phase: hexane/isopropanol 95/5, retention times (min):
21.6 (S, major stereoisomer), 37.5 (R, minor stereoisomer).
(S)-3-(2-Bromophenoxy)-3-p-tolylpropan-1-ol (3ce). (Scheme 5)
Using the general procedure, tris(2-bromophenyl)borate (237.1 mg,
0.45 mmol) (2e) in THF (1.0 mL) was added at room temperature
to a solution of (S)-2-p-tolyloxetane (1c) (44.4 mg, 0.3 mmol) in
THF (0.5 mL). After 20 min at room temperature, the crude mixture
was purified by column chromatography eluting with hexanes/
3-Phenyl-3-(2-chlorophenoxy)-N-(4-methylphenylsulfonyl)-pro-
panamine (7ad). (Entry 5, Table 2) Using the general procedure,
tris(2-chlorophenyl)borate (2d) (196.0 mg, 0.5 mmol) in CH2Cl2
(1.0 mL) was added at room temperature to a solution of 6a (86.1
mg, 0.3 mmol) in CH2Cl2 (0.5 mL). After 24 h at 40 °C the crude
mixture was purified by column chromatography eluting with
hexanes/AcOEt 8:2 to give compound 7ad (112.1 mg, 90%) as an
1
oil. H NMR (250 MHz, CDCl3) δ 2.00-2.18 (m, 2H); 2.38 (s,
3H); 3.05-3.26 (m, 2H); 5.25 (dd, 1H, J1 ) 6.3 Hz, J2 ) 4.5 Hz);
5.46-5.55 (m, 1H, NH); 6.55 (d, 1H, J ) 8.3 Hz); 6.80 (t, 1H, J
) 7.5 Hz); 6.95 (t, 1H, J ) 7.5 Hz); 7.08-7.36 (m, 8H); 7.73 (d,
2H, J ) 8.0 Hz). 13C NMR (62.5 MHz, CDCl3) δ 21.5, 37.4, 40.1,
79.7, 114.8, 121.7, 122.8, 125.5, 127.2, 127.5, 128.0, 128.8, 129.6,
130.1, 136.8, 139.6, 143.2, 152.6. Anal. Calcd for C22H22ClNO3S:
C, 63.53; H, 5.33. Found: C, 63.21; H, 5.14.
AcOEt 8:2 to give compound 3ce (80.6 mg, 84%) as an oil. [R]20
D
) +37.0 (c 0.5, CHCl3). 1H NMR (250 MHz, CDCl3) δ 2.08-2.35
(m, 5H); 2.42-2.58 (br, 1H); 3.78-3.99 (m, 2H); 5.40 (dd, 1H, J1
) 8.2, Hz, J2 ) 4.4 Hz); 6.65-6.77 (m, 2H); 6.95-7.30 (m, 5H);
7.49 (d, 1H, J ) 7.8 Hz). 13C NMR (62.5 MHz, CDCl3) δ 21.2,
41.1, 59.9, 79.7, 114.9, 121.9, 125.7, 128.2, 129.1, 129.5, 133.2,
137.6, 154.0. Anal. Calcd for C16H17BrO2: C, 59.83; H, 5.33. Found:
C, 59.88; H, 5.28. Enantiomeric ratio determined by chiral HPLC
(Chiralcel OD-H), flow rate: 0.5 mL/min, mobile phase: hexane/
isopropanol 95/5, retention times (min): 22.1 (S, major stereoiso-
mer), 31.4 (R, minor stereoisomer).
General Procedure for the Ring Opening of Azetidines. (Table
2) A solution of aryl borate (0.5 mmol) in CH2Cl2 (1.0 mL) was
added to a stirred solution of azetidine (0.3 mmol) in CH2Cl2 (0.5
mL). The mixture was allowed to react at 40 °C and was
quenched with brine (2.0 mL) after complete consumption of
the starting azetidine (24 h). The solution was diluted with Et2O
or CH2Cl2 (20 mL) and washed with brine. Evaporation of the
dried organic solution afforded a crude reaction mixture that
was purified by silica gel column chromatography to give the
pure compounds of type 7.
3-Phenyl-3-(2-fluorophenoxy)-N-(4-methylphenylsulfonyl)-pro-
panamine (7ac). (Entry 6, Table 2) Using the general procedure,
tris(2-fluorophenyl)borate (2c) (177.0 mg, 0.5 mmol) in CH2Cl2
(1.0 mL) was added at room temperature to a solution of azetidine
6a (86.1 mg, 0.3 mmol) in CH2Cl2 (0.5 mL). After 24 h at 40 °C
the crude mixture was purified by column chromatography eluting
with hexanes/AcOEt 8:2 to give compound 7ac (110.2 mg, 92%)
as an oil. 1H NMR (250 MHz, CDCl3) δ 1.98-2.12 (m, 2H); 2.38
(s, 3H); 3.00-3.30 (m, 2H); 5.18 (dd, 1H, J1 ) 8.0 Hz, J2 ) 4.3
Hz); 5.26-5.32 (m, 1H, NH); 6.59-6.68 (m, 1H); 6.78-6.85 (m,
2H); 6.96-7.05 (m, 1H); 7.12 -7.46 (m, 7H); 7.73 (d, 2H, J )
8.2 Hz). 13C NMR (62.5 MHz, CDCl3) δ 21.5, 37.7, 40.2, 80.1,
116.0, 116.3, 117.1, 121.6, 121.7, 125.7, 127.2, 128.0, 128.5, 128.7,
129.7, 136.7, 140.1, 143.3. Anal. Calcd for C22H22FNO3S: C, 66.15;
H, 5.55. Found: C, 65.96; H, 5.48.
3-Phenyl-3-(4-(trifluoromethyl)phenoxy)-N-(4-methyl phenyl-
sulfonyl)-propanamine (7ah). (Entry 7, Table 2) Using the general
procedure, tris(p-(trifluoromethyl)phenyl)borate (2h) (247.0 mg, 0.5
mmol) in CH2Cl2 (1.0 mL) was added at room temperature to a
solution of azetidine 6a (86.1 mg, 0.3 mmol) in CH2Cl2 (0.5 mL).
The mixture was allowed to react for 24 h at 40 °C. After the usual
workup, the crude mixture was purified by column chromatography
eluting with hexanes/AcOEt 8:2 to give compound 7ah (101 mg,
75%) as an oil. 1H NMR (250 MHz, CDCl3) δ 1.93-2.18 (m, 2H);
2.36 (s, 3H); 3.00-3.20 (m, 2H); 5.18-5.28 (m, 2H); 6.79 (d, 2H,
J ) 8.5 Hz); 7.16-7.32 (m, 7H); 7.36 (d, 2H, J ) 8.5 Hz); 7.70
(d, 2H, J ) 8.2 Hz). 13C NMR (62.5 MHz, CDCl3) δ 21.5, 38.1,
39.8, 77.5, 115.7, 125.7, 126.7, 126.8, 127.0, 127.1, 128.0, 128.9,
129.7, 136.5, 140.0, 143.6. Anal. Calcd for C23H22F3NO3S: C, 61.46;
N, 3.12; H, 4.93. Found: C, 61.56; N, 3.20; H, 4.85.
3-Phenyl-3-(3-chlorophenoxy)-N-(4-methylphenyl sulfonyl)-pro-
panamine (7aj). (Entry 2, Table 2) Using the general procedure,
tris(3-chlorophenyl)borate (2j) (196.0 mg, 0.5 mmol) in CH2Cl2
(1.0 mL) was added at room temperature to a solution of (S)-6a
(86.1 mg, 0.3 mmol) in CH2Cl2 (0.5 mL). The mixture was allowed
to react for 24 h at 40 °C and then purified by column chroma-
tography eluting with hexanes/AcOEt 8:2 to give compound 7aj
1
(80.9 mg, 65%) as a semisolid. H NMR (250 MHz, CDCl3) δ
1.93-2.18 (m, 2H); 2.40 (s, 3H); 3.03-3.24 (m, 2H); 4.62-4.73
(m, 1H, NH); 5.12 (dd, 1H, J1 ) 8.3 Hz, J2 ) 4.5 Hz); 6.61 (dd,
1H, J1 ) 8.3 Hz, J2 ) 1.8 Hz); 6.71-6.75 (m, 1H); 6.83 (dd, 1H,
J1 ) 8.3 Hz, J2 ) 0.8 Hz); 7.05 (t, 1H, J ) 8.3 Hz); 7.12-7.36
(m, 7H); 7.68 (d, 1H, J ) 8.2 Hz). 13C NMR (62.5 MHz, CDCl3)
δ 21.5, 38.0, 40.0, 77.9, 114.0, 116.5, 121.3, 125.6, 127.1, 128.0,
128.8, 129.7, 130.1, 134.6, 136.4, 140.1, 143.6, 158.2. Anal. Calcd
for C22H22ClNO3S: C, 63.53; H, 5.33. Found: C, 63.32; H, 5.28.
Enantiomeric ratio determined by chiral HPLC (Chiralcel OD-H),
flow rate: 0.5 mL/min, mobile phase: hexane/isopropanol 85/15,
retention times (min): 36.7 (52%), 56.9 (48%).
3-Phenyl-3-(2-bromophenoxy)-N-(4-methyl phenylsulfonyl)-pro-
panamine (7ae). (Entry 8, Table 2) Using the general procedure,
tris(2-bromophenyl)borate (2e) (261.9 mg, 0.5 mmol) in CH2Cl2
(1.0 mL) was added at room temperature to a solution of compound
6a (86.1 mg, 0.3 mmol) in CH2Cl2 (0.5 mL). After 24 h at 40 °C
the crude mixture was purified by column chromatography eluting
with hexanes/AcOEt 8:2 to give compound 7ae (96 mg, 65%) as
an amorphous solid. 1H NMR (250 MHz, CDCl3) δ 1.99-2.17 (m,
2H); 2.38 (s, 3H); 3.05-3.21 (m, 2H); 5.225-5.30 (m, 1H);
9006 J. Org. Chem. Vol. 73, No. 22, 2008

Ring Opening of 2-Aryl Oxetanes and Azetidines
5.54-5.58 (m, 1H, NH); 6.53 (d, 1H, J ) 7.5 Hz); 6.68-6.77 (m,
1H); 6.91-7.02 (m, 1H); 7.08-7.27 (m, 7H); 7.47-7.53 (m, 1H);
7.74 (d, 2H, J ) 8.2 Hz). 13C NMR (62.5 MHz, CDCl3) δ 21.5,
37.4, 40.0, 79.6, 114.6, 122.2, 125.5, 127.2, 127.9, 128.3, 128.8,
129.6, 133.2, 136.8, 139.5, 143.2, 153.7. Anal. Calcd for
C22H22BrNO3S: C, 57.39; H, 4.82. Found: C, 57.45; H, 4.76.
(2S*,3S*)-2-Hydroxy-3-phenyl-3-(3-chlorophenoxy)-N-(4-meth-
ylphenylsulfonyl)-propanamine (8dj). (Scheme 6) Using the general
procedure, tris(3-chlorophenyl)borate (2j) (352 mg, 0.9 mmol) in
CH2Cl2 (1.0 mL) was added at room temperature to a solution of
azetidinol 6d (91 mg, 0.3 mmol) in CH2Cl2 (1.0 mL). The mixture
was allowed to react for 24 h at 40 °C and then purified by column
chromatography eluting with hexanes/AcOEt 8:2 to give compound
and diethylazodicarboxylate (31.3 mg, 0.18 mmol) under argon.
The mixture was allowed to react for 18 h at room temperature
Column chromatography eluting with hexanes/AcOEt 7:3 afforded
1
pure 11 (23 mg, 84%), as a colorless liquid. H NMR (250 MHz,
CDCl3) δ 2.31-2.45 (m, 2H); 3.94-4.19 (m, 1H); 4.33-4.56 (m,
1H); 4.94-5.13 (m, 1H); 6.75-7.08 (m, 4H); 7.14-7.50 (m, 5H).
13C NMR (62.5 MHz, CDCl3) δ 39.1, 69.8, 82.3, 121.3, 122.0,
123.3, 125.8, 127.8, 128.5, 141.6, 151.4, 153.2. Anal. Calcd for
C15H12O2: C, 80.34; H, 5.39. Found: C, 80.06; H, 5.27. Enantiomeric
ratio determined by chiral HPLC (Chiralcel OB-H), flow rate: 0.5
mL/min, mobile phase: hexane/isopropanol 97/3, retention times
(min): 15.8 (S, minor stereoisomer), 25.7 (R, major stereoisomer).
1
8dj (84 mg, 65%) as an oil. H NMR (250 MHz, CDCl3) δ 2.42
Acknowledgment. This work was supported by the Ministero
dell’Universita` e della Ricerca (Progetti di Ricerca di Interesse
Nazionale, PRIN 2006) and by the University of Pisa.
(s, 3H); 2.88-2.98 (m, 3H); 3.91-3.97 (m, 1H); 4.89-4.96 (m,
1H); 5.09 (d, 1H, J ) 6.0 Hz); 6.65-6.70 (m, 1H), 6.85-6.92 (m,
2H); 7.08 (t, 1H, J ) 7.5 Hz), 7.25-7.43 (m, 8H), 7.68 (d, 2H, J
) 8.1 Hz). 13C NMR (62.5 MHz, CDCl3) δ 21.5, 43.9, 73.4, 81.38,
99.9, 114.0, 116.7, 121.8, 126.8, 127.1, 128.9, 129.0, 129.8, 130.2,
136.1, 143.6. Anal. Calcd for C22H22ClNO4S: C, 61.18; H, 5.13.
Found: C, 60.95; H, 5.05.
Supporting Information Available: Text giving detailed
experimental procedures and characterization data for all new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
(R)-2-Phenyl-1,5-benzodioxepine (11). (Scheme 8) To a stirred
solution of compound 3af (29 mg, 0.12 mmol) in anhydrous THF
(0.5 mL) were added at rt triphenylphosphine (62.9 mg, 0.24 mmol)
JO801568A
J. Org. Chem. Vol. 73, No. 22, 2008 9007