A synthesis of 6-azabicyclo[3.2.1]octanes. The role of N-substitution

Article abstract of DOI:10.1021/jo702444c

(Chemical Equation Presented) The intramolecular cyclization reactions of aziridines with π-nucleophiles can be a useful route to a number of heterocyclic and carbocyclic ring systems. We were particularly interested in the use of this cyclization reaction for the synthesis of 6-azabicyclo[3.2.1] octanes. We report here the development of a new synthesis of the aziridine necessary for the aziridine-π-nucleophile cyclization. We also report on the cyclization of aziridines with three different substitutions on the aziridine nitrogen. We have found that N-diphenylphospinyl and N-H aziridines, while participating in the initial ring-opening reaction, do not lead to the desired bicyclic ring systems. In contrast, a nosyl group on the aziridine nitrogen leads efficiently to the bicyclic ring system and can be readily deprotected.

Full text of DOI:10.1021/jo702444c

A Synthesis of 6-Azabicyclo[3.2.1]octanes. The Role of
N-Substitution
Aravinda B. Pulipaka and Stephen C. Bergmeier*
Department of Chemistry and Biochemistry, Clippinger Laboratories, Ohio UniVersity, Athens, Ohio 45701
bergmeis@ohio.edu
ReceiVed NoVember 14, 2007
The intramolecular cyclization reactions of aziridines with π-nucleophiles can be a useful route to a
number of heterocyclic and carbocyclic ring systems. We were particularly interested in the use of this
cyclization reaction for the synthesis of 6-azabicyclo[3.2.1]octanes. We report here the development of
a new synthesis of the aziridine necessary for the aziridine-π-nucleophile cyclization. We also report
on the cyclization of aziridines with three different substitutions on the aziridine nitrogen. We have
found that N-diphenylphospinyl and N-H aziridines, while participating in the initial ring-opening reaction,
do not lead to the desired bicyclic ring systems. In contrast, a nosyl group on the aziridine nitrogen leads
efficiently to the bicyclic ring system and can be readily deprotected.
Introduction
The 6-azabicyclo[3.2.1]octane skeleton is found in a wide
variety of naturally occurring and synthetic pharmacologically
active molecules. Some examples include natural products such
as the GABAA receptor antagonist securinine1,2 and analgesic
aphanorphine.3 Nonnatural molecules containing the 6-azabi-
cyclo[3.2.1]octane system are also well-known. These range
from very simple molecules such as the bicyclic proline
analogue 14 to the more complex aphanorphine analogue 2.5
Other examples include 3, which was prepared as a ring-deleted
analogue of the alkaloid methyllycaconitine,6 and 4, a potent
* To whom correspondence should be addressed. Phone: 740-517-8462.
Fax: 740-593-0148.
(1) Saito, S.; Kotera, K.; Shigematsu, N.; Ide, A.; Sugimoto, N.; Horii,
Z.; Hanaoka, M.; Yamawaki, Y.; Tamura, Y. Tetrahedron 1963, 19, 2085-
2099.
(2) Horii, Z.; Ikeda, M.; Yamawaki, Y.; Tamura, Y.; Saito, S. Tetrahe-
dron 1963, 19, 2101-2110.
FIGURE 1. Azabicyclo[3.2.1]octanes.
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Lett. 1988, 29, 4381-4384.
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R. I.; Shishkin, O. V.; Komarov, I. V. Tetrahedron: Asymmetry 2006, 17,
252-258.
inhibitor of dopamine reuptake (Figure 1).7 We were interested
in such molecules as potential ligands for the nicotinic acetyl-
choline receptor.
We have recently reported on a method for the synthesis of
5-substituted 6-tosylazabicyclo[3.2.1]octanes.8,9 This method
involves the intramolecular cyclization of a π-nucleophile with
(5) Takeda, M.; Inoue, H.; Noguchi, K.; Honma, Y.; Kawamori, M.;
Tsukamoto, G.; Yamawaki, Y.; Saito, S.; Aoe, K.; Date, T.; Nurimoto, S.;
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10.1021/jo702444c CCC: $40.75 © 2008 American Chemical Society
Published on Web 01/23/2008
1462
J. Org. Chem. 2008, 73, 1462-1467

A Synthesis of 6-Azabicyclo[3.2.1]octanes
SCHEME 1. Attempted Synthesis To Make Unprotected
Azabicyclo[3.2.1]octane
activate the aziridine toward nucleophilic attack by the π-nu-
cleophile. Second this activating group must allow the formation
of the bicyclic ring system. Finally, the activating group should
be readily removed without harming the products, especially
the benzylic C-N bond. In considering activating groups on
the nitrogen, three general classes generally have been used.21
The first of these are N-carbonyl-type activating groups. Of this
group, amides (e.g., benzamide, trifluoroacetamide) and car-
bamates (e.g., Cbz, Boc) are the most widely used. This type
of activating group can be problematic in activating an aziri-
dine.22 Under acidic conditions, the carbonyl will often act as
a nucleophile and open the aziridine ring leading to oxazoline
ring systems.23-25 Consequently we do not plan to examine this
type of activating group for this reaction. Sulfonyl activating
groups are excellent for acid-catalyzed aziridine reactions as
there is no carbonyl to subsequently open the aziridine ring.
The subsequent removal of sulfonyl activating groups is largely
dependent upon the alkyl or aryl group attached to the sulfonyl.
We have already seen that removal of the toluenesulfonyl group
under strongly reducing conditions is not viable for compounds
such as 7a. The p-nitrophenylsulfonyl (Ns) group is reported
to be useful in aziridine ring-opening reactions26 and readily
removed via thiolysis.27 This should be an excellent choice of
activating group in that it is acid stable and has been used to
activate aziridines for ring opening. Another class of aziridine
nitrogen activating groups that should be amenable to these
reaction conditions and is readily removed is the diphenylphos-
phinyl (Ph2P(O) or Dpp) group. The Dpp group has been used
to activate aziridine rings toward nucleophilic ring opening.28-31
an N-tosyl aziridine. This reaction proceeds via an initial attack
of the double bond on the aziridine ring leading to a carboca-
tionic intermediate 6. The nitrogen then cyclizes on the stabilized
carbocation to provide the bicyclic product 7a. This method
works well with both an aryl- and an alkyl-substituted olefin
as the π-nucleophile. In related cyclizations, substitution on the
aromatic ring is generally well tolerated. For our project on the
conversion of such molecules into ligands for the nAChR we
wished to remove the toluenesulfonyl group to generate 7b and
replace this protecting group with an alkyl or aryl group yielding
8 (Scheme 1).
Our attempts to remove the toluenesulfonyl group of 7a under
a wide variety of conditions failed to provide 7b in reasonable
yield.10-13 It seems likely that the reductive conditions used to
remove the tosyl group may also cleave the benzyl-amine bond
giving rise to several products.
Our plan therefore was to examine the use of different
protecting groups on the aziridine nitrogen with respect to the
direct formation of the 6-azabicyclo[3.2.1]octane skeleton. We
would expect that the nature of the group on the aziridine ring
nitrogen should be quite important, both with respect to the
initial ring opening as well as to the subsequent formation of
the bicyclic ring system. The need for an electron-stabilizing
group on the nitrogen in order to promote the initial ring opening
(5 f 6) is well documented.14-20 It is not clear what role this
group would play in the subsequent ring closure to form 7a.
(21) Greene, T. W.; Wuts, P. G. M. ProtectiVe groups in organic
synthesis, 3rd ed.; John Wiley & Sons: New York, 1999.
(22) Fundy, S. L. Ohio State University 2000.
We have examined a number of different substitutions on the nitrogen of
the aziridine in the related aziridine-allylsilane cyclization. Of the groups
examined in this study, the carbonyl-based activating groups (Cbz, benzoyl,
and phenylacetyl) provided product in the lowest yields (17-35%). At room
temperature a significant distinction was found between aryl sulfonyl groups
that were either electron rich (e.g., 4-OMeC6H4) and those that were electron
poor (e.g., Ns). The Ns group provided no bicyclic product only the
monocyclic product in 96% yield. The 4-OMeC6H4SO2 in contrast gave a
60:40 mix of monocyclic product to bicyclic product. However, at -50 °C
we obtain a roughly 1:1 mixture of the olefin to bicycle. This suggested
that at room temperature, the better electron-stabilizing group (i.e., Ns) more
readily undergoes a â-elimination to provide the monocyclic product while
the 4-OMe derivative does not. An examination of additional arylsulfonyl
groups (with intermediate electron stabilizing ability) also indicated a
roughly 1:1 ratio of the monocycle to bicycle ratio. This indicated that the
stability of the sulfonamide anion had no significant effect on the initial
bicycle formation.
Results and Discussion
Our goal of changing the activating group on the nitrogen of
the aziridine so as to still generate the 6-azabicyclo[3.2.1]octane
ring and then remove that activating group requires a consid-
eration of multiple factors. This activating group must first
(10) Bergmeier, S. C.; Seth, P. P. Tetrahedron Lett. 1999, 40, 6181-
6184.
(11) Hamada, T.; Nishida, A.; Yonemitsu, O. J. Am. Chem. Soc. 1986,
108, 140-145.
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Chem. 1987, 52, 3319-3322.
(23) Cardillo, G.; Gentilucci, L.; Tolomelli, A.; Tomasini, C. Tetrahedron
Lett. 1997, 38, 6953-6956.
(13) Roemmele, R. C.; Rapoport, H. J. Org. Chem. 1888, 53, 2367-
2371.
(24) Ferraris, D.; Drury, W. J., I.; Cox, C.; Lectka, T. J. Org. Chem.
1998, 63, 4568-4569.
(14) Pearson, W. H.; Lian, B. W.; Bergmeier, S. C. In ComprehensiVe
Heterocyclic Chemistry II, 2nd ed.; Padwa, A., Ed.; Pergamon: Oxford,
UK, 1996; Vol. 1, pp 1-60.
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3088.
(15) Bera, M.; Roy, S. Tetrahedron Lett. 2007, 48, 7144-7146.
(16) Schneider, M.-R.; Mann, A.; Taddei, M. Tetrahedron Lett. 1996,
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2007, 63, 2482-2489.
(27) Fukuyama, T.; Jow, C. K.; Cheung, M. Tetrahedron Lett. 1995,
36, 6373-6374.
(17) Sato, K.; Kozikowski, A. P. Tetrahedron Lett. 1989, 30, 4073-
4076.
(28) Sweeney, J. B.; Cantrill, A. A. Tetrahedron 2003, 59, 3677-3690.
(29) Cantrill, A. A.; Osborn, H. M. I.; Sweeney, J. Tetrahedron 1998,
54, 2181-2208.
(18) Ungureanu, I.; Klotz, P.; Mann, A. Angew. Chem., Int. Ed. 2000,
39, 4615-4617.
(19) Yadav, J. S.; Reddy, B. V. S.; Abraham, S.; Sabitha, G. Tetrahedron
Lett. 2002, 43, 1565-1567.
(30) Cantrill, A. A.; Sweeney, J. B. Synlett 1995, 1277-1279.
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147.
(20) Hu, X. E. Tetrahedron 2004, 60, 2701-2743.
J. Org. Chem, Vol. 73, No. 4, 2008 1463

Pulipaka and Bergmeier
SCHEME 4. Synthesis of Aziridines 5b, 5c, and 5d
SCHEME 2. Initial Attempt To Prepare Differentially
Substituted Aziridines
SCHEME 3. Retrosynthesis of Aziridine 5
aldehyde 13 (X ) H) via sulfur ylide chemistry. This aldehyde
should be available from cyclopentene 14, via an ozonolysis/
functional group modification sequence.
The reduction of this route to practice is shown in Scheme
4. The known cyclopentene 14 was prepared by the reported
route via addition of PhMgBr to cyclopentanone followed by
dehydration to provide 1-phenylcyclopentene 14.37 Ozonolysis
of 14 followed by treatment of the ozonide with excess Et3N
provided the keto acid in excellent yield.38 Subsequent esteri-
fication with HCl and methanol provided the ester 16 in 81%
overall yield. Wittig reaction of ketoester 16 provided the
olefinic ester 17 in 91% yield. DIBAL-H reduction of this ester
in dichloromethane at -78 °C gave a 90% yield of the
corresponding aldehyde.39 The aldehyde was directly converted
into epoxide 12 in 65% yield by reaction with dimethylsulfo-
nium methylide.40-43 Ring opening of epoxide with sodium
azide followed by ring closing with Ph3P gave the aziridine 5b
in 88% overall yield. This aziridine was then treated with
p-nitrophenylsulfonyl chloride and diphenylphosphinyl chloride
to provide the N-Ns and N-Dpp aziridines 5c and 5d in 93%
and 85% yields, respectively.
This group is readily removed under acidic conditions.32-34
Given our need to only use activating groups that could be
readily removed we have chosen to use only the Ns and Dpp
groups. In addition to their easy removal, we have also
successfully used these groups in previous aziridine-π-nucleo-
phile cyclizations.22
Aziridine 5a was previously prepared from aziridine 9 via a
five-step sequence. As shown in Scheme 2, an initial ring
opening/ring closing sequence was used to convert 9 into olefinic
aziridine 11.35 This olefin was then converted to 5a via a
Suzuki-Miyaura cross-coupling reaction with 1-bromostyrene.36
The modification of this reaction sequence to use either the
Ns or Dpp groups was unsuccessful. We were able to prepare
aziridines corresponding to 9 in which the toluenesulfonyl group
was replaced with either a Ns or a Dpp group. However, with
both aziridines (N-Ns and N-Dpp) the initial ring opening of
aziridine 9 failed to provide significant amounts of ring-opened
product 10.
Given our interest in exploring different activating groups
on the nitrogen of the aziridine ring we decided to develop an
alternate synthesis of aziridine 5 that proceeds through an
N-unsubstituted aziridine. Such a synthetic route would be
amenable to the introduction of a number of different activating
groups on the aziridine nitrogen. As outlined in Scheme 3, the
requisite aziridine 5b (R ) H) should be readily obtained from
epoxy olefin 12 via an azide opening/ring formation sequence.
The epoxide should be available from the corresponding
With the necessary aziridine substrates in hand we examined
the cyclization reactions using different reaction conditions
(Table 1). As noted previously (entry 1) the N-Ts aziridine 5a
provides a good yield of the desired bicyclic product upon
treatment with 300 mol % of BF3‚OEt2 at room temperature
for 2 h.9 The use of 100 mol % of BF3‚OEt2 provides roughly
the same yield.
We first examined the N-Ns aziridine 5c under this set of
reaction conditions. All reactions were carried out in CD2Cl2
(37) Garbisch, E. W. J. Org. Chem. 1961, 26, 4165-4166.
(38) Hon, Y.-S.; Lin, S.-W.; Lu, L.; Chen, Y.-J. Tetrahedron 1995, 51,
5019-5034.
(32) Ramage, R.; Atrash, B.; Hopton, D.; Parrott, M. J. J. Chem. Soc.,
Perkin Trans. 1 1985, 1217-1226.
(33) Ramage, R.; Hopton, D.; Parrott, M. J.; Kenner, G. W.; Moore, G.
A. J. Chem. Soc., Perkin Trans. 1 1984, 1357-1370.
(34) Kenner, G. W.; Moore, G. A.; Ramage, R. Tetrahedron Lett. 1976,
3623.
(39) Zhong, W. T.; Paquette, L. A. J. Org. Chem 1986, 51, 5232-5234.
(40) Borredon, E.; Delmas, M.; Gaset, A. Tetrahedron Lett. 1982, 23,
5283-5286.
(41) Corey, E. J.; Chaykovsky, M. J. J. Am. Chem. Soc. 1965, 87, 1353-
1364.
(42) Kumar, A.; Singh, R.; Mandal, A. K. Synth. Commun. 1982, 12,
(35) Bergmeier, S. C.; Seth, P. P. J. Org. Chem. 1997, 62, 2671-2674.
(36) Lapinsky, D. J.; Bergmeier, S. C. Tetrahedron Lett. 2001, 42, 8583-
8586.
613-619.
(43) Rosenberger, M.; Jackson, W. HelV. Chim. Acta 1980, 63, 1665-
1674.
1464 J. Org. Chem., Vol. 73, No. 4, 2008

A Synthesis of 6-Azabicyclo[3.2.1]octanes
TABLE 1. Intramolecular Cyclization of Aziridines with a
π-Nucleophile
SCHEME 5. Removal of the Ns Group
initial cyclization has occurred and the Dpp group has been
removed. Since the Dpp group can be removed by acid it was
not clear if the Dpp group was removed before or after the
cyclization occurred. However, on the basis of this result we
decided to examine the N-H aziridine 5b in this cyclization
reaction.
The use of N-H or N-alkyl aziridines in reactions with
π-nucleophiles has not been observed to date. Consequently such
cyclizations are of significant interest. Reaction of aziridine 5b
with BF3‚OEt2 provided no identifiable product of any kind.
However, the reaction of 5b with both TFA and B(C6F5)3 did
provide reasonable (65% and 73%) isolated yields of the
monocyclic product 19b as a single olefin regioisomer. To the
best of our knowledge this is the first example of an unactivated
aziridine being opened by a π-nucleophile. Clearly, the more
basic nature of the amine generated from the N-H aziridine
seems to have prevented the formation of the bicyclic ring
system.
entry substrate
conditionsa
products
1
2
5a
5a
5b
5b
5b
5b
5b
5b
5c
5c
5c
5c
5c
5c
5d
5d
5d
5d
5d
BF3‚OEt2, 300 mol %, 2 h
BF3‚OEt2, 100 mol %, 2 h
BF3‚OEt2, 15 mol %, 8 h
BF3‚OEt2, 100 mol %, 8 h
B(C6F5)3, 15 mol %, 24 h
B(C6F5)3, 100 mol %, 8 h
7a (63%)b
7a (60%)b
2
3
4
5
6
7
8
9
no reaction
decomposition
no reaction
19b (73%)b
CF3COOH, 15 mol %, 24 h 5b:19b (1:1)a
CF3COOH, 100 mol %, 8 h 19b (65%)b
BF3‚OEt2, 15 mol %, 24 h
BF3‚OEt2, 100 mol %, 2 h
B(C6F5)3, 15 mol %, 24 h
B(C6F5)3, 100 mol %, 2 h
7c:19c:20c (1.5:1:1.7)a
7c:19c:20c (1.8:1:1.8)a
5c:7c (3:2)a
10
11
12
13
14
15
16
17
18
7c (95%)b
CF3COOH, 15 mol %, 24 h no reaction
CF3COOH, 100 mol %, 2 h 7c:19c:20c (5.3:1:1.3)a
BF3‚OEt2, 15 mol %,24 h
BF3‚OEt2, 100 mol %, 8 h
B(C6F5)3, 15 mol %, 24 h
B(C6F5)3, 100 mol %, 10 h
CF3COOH, 15 mol %, 8 h
5d:19d:20d (1:3:6.5)a
19d:20d (2.3:1)(55%)b
no reaction
19d:20d (2:1) (72%)b
19b (64%)b
Having identified an aziridine substitution that leads to the
bicyclic product 7, we next examined the removal of the
aziridine substitution to obtain the unsubstituted bicycle 7b.
Treatment of 7c with PhSH/K2CO3 cleanly provided the desired
product 7b (Scheme 5) in 70% isolated yield.
1
a Product ratio determined by H NMR. b Isolated yield
in an NMR tube so that reaction progress could be directly
monitored by 1H NMR. The initial reaction of 5c with a catalytic
amount of BF3‚OEt2 provided a 1:2 mixture of the desired
bicycle (7c) to a mixture of two isomeric monocyclic products,
19c and 20c. Increasing the amount of BF3‚OEt2 to 100 mol %
provided essentially the same product ratio. While additional
Lewis acids might be considered, our previous experience
suggests that BF3‚OEt2 and related Lewis acids are the optimum
catalyst for this type of reaction.44 On the basis of the work of
Yudin et al. the Lewis acid B(C6F5)3 was examined and provided
considerably better results.45 Treatment of 5c with 15 mol %
of B(C6F5)3 showed only a 3:2 mixture of starting material to
bicyclic product. However, none of the monocyclic product was
observed. Increasing the amount of B(C6F5)3 to 100 mol %
provided the bicyclic product 7c in a 95% isolated yield. We
also examined the use of a protic acid with these substrates.
The use of a catalytic amount of trifluoroacetic acid yielded no
product, while increasing the amount of acid did lead to the
formation of bicycle 7c as a 5:2 mixture with the monocyclic
product 19c and 20c.
Unlike the N-Ts and N-Ns aziridines, the N-Dpp aziridine
5d provided none of the desired bicyclic product 7d. Reaction
of 5d with a catalytic amount of BF3‚OEt2 provided only a
mixture of starting material and monocyclic products 19d and
20d. Increasing the amount of BF3‚OEt2 to 100 mol % provided
only the monocyclic products 19d and 20d in a 2:1 ratio. The
mixture of compounds 19d and 20d was isolated in 55% yield.
The use of 100 mol % of B(C6F5)3 again provided only a 2:1
mixture of 19d to 20d albeit in a better isolated yield than with
the BF3‚OEt2. Interestingly, the use of a protic acid (TFA)
instead of a Lewis acid provided 19b, a product in which an
Conclusions
In summary, we discovered that N-substitution plays an
important role in the intramolecular cyclization of aziridines
with π-nucleophiles. Both Dpp and N-H aziridines underwent
monocyclization. Cyclization of the N-H aziridine is unique
in that ring opening of an unactivated aziridine with a π-nu-
cleophile has not been observed to date. An aziridine protected
with a nosyl group successfully underwent ring opening and
cyclization to provide the desired 6-azabicyclo[3.2.1]octane
skeleton. The conversion of the N-H product into a variety of
substituted bicyclic compounds is underway and results will be
reported in due course.
Experimental Section
Methyl 5-Oxo-5-phenylpentanoate (16). Ozone was passed
through a solution of 1-phenylcyclopentene 1437 (15 g, 0.1 mol) in
CH2Cl2 (200 mL) at -78 °C until a blue color appeared. The
reaction mixture was then treated with Et3N (42.1 g, 0.42 mol)
and the reaction stirred at room temperature overnight. The reaction
mixture was acidified with 1 M HCl and the brown precipitate that
formed was filtered, washed with water, and dried under vacuum
to provide 16.5 g (83%) of 5-oxo-5-phenylpentanoic acid, which
matched the reported spectra.38 To a 0 °C solution of the crude
acid in MeOH (100 mL) was added acetyl chloride (7.2 g, 96.7
mmol), then the reaction was warmed to room temperature and
stirred overnight. This reaction was diluted with CH2Cl2 (200 mL)
and washed with saturated NaHCO3 solution, brine, and water. The
organic layer was dried over MgSO4, filtered, and concentrated to
provide 17.1 g (96%) of ester 16 as a clear oil: 1H NMR (CDCl3,
300 MHz) δ 7.94 (d, 2H, J ) 7.1 Hz), 7.42 (m, 3H), 3.67 (s, 3H),
3.02 (t, 2H, J ) 6.2 Hz), 2.42 (t, 2H, J ) 7.2 Hz), 2.03 (m, 2H, J
(44) Bergmeier, S. C.; Seth, P. P. J. Org. Chem. 1999, 64, 3237-3243.
(45) Watson, I. D. G.; Yudin, A. K. J. Org. Chem. 2003, 68, 5160-
5167.
J. Org. Chem, Vol. 73, No. 4, 2008 1465

Pulipaka and Bergmeier
) 7.1 Hz). 13C NMR (CDCl3, 75 MHz) δ 199.3, 173.6, 136.9,
132.9, 128.6, 128.3, 127.9, 51.5, 37.4, 33.1, 19.4.
provide 538 mg (95%) of aziridine 5b as a clear oil: 1H NMR
(CDCl3, 300 MHz) δ 7.24 (m, 5H), 5.26 (s, 1H), 5.05 (s, 1H), 2.52
(t, 2H, J ) 7.5 Hz), 1.88 (m, 1H), 1.71 (m, 1H), 1.57 (m, 2H),
1.38 (m, 2H), 1.27 (m, 1H). 13C NMR (CDCl3, 75 MHz) δ 148.4,
141.3, 128.2, 127.2, 126.1, 112.3, 35.1, 34, 30.0, 26.2, 24.9. HRMS
calcd for C13H17N‚Na+ 210.1259, found 210.1248.
1-Nosyl-2-(4-phenylpent-4-enyl)aziridine (5c). p-Nitrophenyl-
sulfonyl chloride (0.14 g, 0.64 mmol) was added to a -78 °C
solution of aziridine 5b (0.1 g, 0.53 mmol) and Et3N (0.11 g, 1.06
mmol) in CH2Cl2 (1 mL). After 5 min at -78 °C, the reaction was
warmed to 0 °C over 20 min. The reaction was then diluted with
CH2Cl2 and the organic phase was washed with 1 M HCl and
saturated NaHCO3, dried (MgSO4), concentrated, and chromato-
graphed (5% EtOAc in hexanes) to provide 184 mg (93%) of
aziridine 5c: 1H NMR (CDCl3, 300 MHz) δ 8.3 (d, 2H, J ) 8.97
Hz), 8.08 (d, 2H, J ) 9 Hz), 7.32 (m, 5H), 5.24 (s, 1H), 4.98 (s,
1H), 2.83 (m, 1H), 2.75 (d, 1H, J ) 7.0 Hz), 2.47 (t, 2H, J ) 6.7
Hz), 2.15 (d, 1H, J ) 4.7 Hz), 1.61 (m, 1H), 1.35 (m, 3H). 13C
NMR (CDCl3, 75 MHz) δ 150.5, 147.6, 143.9, 129.2, 128.4, 127.6,
126.0, 124.2, 112.8, 41.2, 34.6, 34.4, 30.7, 25.3. HRMS calcd for
C19H20N2O4S‚Na+ 372.1144, found 372.1134.
1-Diphenylphosphinyl-2-(4-phenylpent-4-enyl)aziridine (5d).
To a -78 °C solution of aziridine 5b (0.1 g, 0.53 mmol) and DMAP
(6.5 mg, 0.053 mmol) in CH2Cl2 (1 mL) were added Et3N (0.213
g, 2.13 mmol) and diphenylphosphinic chloride (0.195 g, 0.828
mmol). The reaction was warmed to 0 °C and stirred 20 min. The
mixture was then diluted with CH2Cl2, and the organic phase was
washed with 1 M HCl and saturated NaHCO3 solution, dried
(MgSO4), concentrated, and chromatographed (10% EtOAc in
hexanes) to provide 175 mg (85%) of pure Dpp protected aziridine
5d: 1H NMR (CDCl3, 300 MHz) δ 7.8 (m, 5H), 7.28 (m, 10H),
5.21 (s, 1H), 4.92 (s, 1H), 2.62 (m, 1H), 2.5 (dd, 1H, J ) 7.6, 5.9
Hz), 2.27 (t, 2H, J ) 7.3 Hz), 1.89 (m, 1H), 1.46 (m, 2H), 1.24
(m, 2H). 13C NMR (CDCl3, 75 MHz) δ 132.3, 131.7, 131.6, 131.5,
128.7, 128.5, 128.4, 128.3, 128.3, 128.2, 127.4, 126.1, 112.5, 51.6,
34.8, 32.1, 29.7, 25.4. HRMS calcd for C25H26NOP‚Na+ 410.1650,
found 410.1645.
(3-Phenylcyclohex-2-enyl)methanamine (19b). To a 0 °C
solution of aziridine 5b (0.02 g, 0.106 mmol) or 5d (0.02 g, 0.052
mmol) in CH2Cl2 (1 mL) was added trifluoroacetic acid (8 µL,
0.106 mmol for 5b or 4 µL, 0.052 mmol for 5d). The reaction was
warmed to room temperature and stirred for 2 h. The reaction was
diluted with CH2Cl2, washed with saturated aq Na2CO3 and brine,
dried (MgSO4), concentrated, and chromatographed (5% EtOAc
in hexanes) to provide 13 mg (65%) from 5b (or 6.2 mg (64%)
from 5d) of 19b as a clear oil: 1H NMR (CDCl3, 300 MHz) δ
7.21 (m, 5H), 6.03 (s, 1H), 2.69 (m, 2H), 2.41 (m, 2H), 2.31 (m,
1H), 1.86 (m, 2H), 1.7 (m, 1H), 1.34 (m, 3H). 13C NMR (CDCl3,
75 MHz) δ 142.4, 138.1, 128.2, 126.8, 125.1, 47.7, 39.7, 27.8, 26.2,
21.8. HRMS calcd for C13H17N‚Na+ 188.1432, found 188.1432.
N-Diphenylphosphinyl(3-phenylcyclohex-2-enyl)metha-
namine (19d) and N-Diphenylphosphinyl(3-phenylcyclohex-3-
enyl)methanamine (20d). To a 0 °C solution of aziridine 5d (0.02
g, 0.052 mmol) in CH2Cl2 (1 mL) was added BF3‚OEt2 (6.5 µL,
0.052 mmol). The reaction was warmed to room temperature and
stirred for 2 h. The reaction was diluted with CH2Cl2, washed with
saturated aq Na2CO3 and brine, dried (MgSO4), concentrated, and
chromatographed (5% EtOAc in hexanes) to provide 11 mg of a
2:1 mixture of 19d and 20d (55%) as a clear oil: 1H NMR (CDCl3,
300 MHz) δ 7.8 (m, 4H), 7.4 (m, 6H), 7.05 (m, 6H), 6.03 (s, 0.3H),
5.95 (m, 0.63H), 2.8 (m, 3H), 2.51 (m, 1H), 2.05 (m, 2H), 1.86
(m, 2H), 1.7 (m, 1H), 1.34 (m, 3H, 2H). 13C NMR (CDCl3, 75
MHz) δ 132.3, 131.7, 131.6, 131.5, 128.7, 128.5, 128.4, 128.3,
128.3, 128.2, 127.4, 126.1, 112.5, 51.6, 34.8, 32.1, 29.7, 25.4.
HRMS calcd for C25H26NOP‚Na+ 410.1650, found 410.1645.
N-(4-Nitrophenylsulfonyl)-5-phenyl-6-azabicyclo[3.2.1]-
octane (7c). B(C6F5)3 (0.453 g, 0.885 mmol) was added to a 0 °C
solution of nosyl aziridine 5c (0.3 g, 0.805 mmol) in CH2Cl2 (3
mL) at 0 °C. The reaction was warmed to room temperature and
Methyl 5-Phenylhex-5-enoate (17). To a slurry of methyltriph-
enylphosphonium bromide (17.8 g, 50 mmol) in THF (100 mL) at
0 °C was added potassium tert-butoxide (5.85 g, 50 mmol). After
1 h of stirring, the reaction was cooled to -78 °C and ester 16 (4.3
g, 20 mmol) was added to the reaction. The solution was warmed
to room temperature and stirred for 30 min. It was then quenched
with saturated aqueous NH4Cl (30 mL) and extracted with Et2O (3
× 50 mL). The combined organic layers were washed with brine,
dried over MgSO4, filtered, concentrated, and chromatographed (5%
EtOAc in hexanes) to provide 3.9 g (91%) of 17 as a clear oil: 1H
NMR (CDCl3, 300 MHz) δ 7.15 (m, 5H), 5.2 (s, 1H), 4.9 (s, 1H),
3.5 (s, 3H), 2.42 (t, 2H, J ) 7.7 Hz), 2.21 (t, 2H, J ) 7.5 Hz), 1.64
(m, 2H, J ) 7.4 Hz). 13C NMR (CDCl3, 75 MHz) δ 128.3, 127.4,
126.1, 112.9, 51.4, 34.6, 33.4, 23.4. HRMS calcd for C13H16O2
204.1150, found 204.1156.
2-(4-Phenylpent-4-enyl)oxirane (12). DIBAL (5.94 mL of a 1
M solution in hexanes, 5.94 mmol) was slowly added to a solution
of ester 17 (1 g, 4.89 mmol) in CH2Cl2 (10 mL) at -78 °C and
stirring was continued for an additional 1 h. The reaction was
quenched by adding methanol (10 mL) at -78 °C and warmed to
room temperature. HCl (1 M, 50 mL) was added and the reaction
was extracted with CH2Cl2 (3 × 25 mL). The combined organic
layers were washed with brine, dried (MgSO4), and concentrated
to provide 0.77 g (90%) of aldehyde, which was used immediately
in the subsequent reaction: 1H NMR (CDCl3, 300 MHz) δ 9.62 (t,
1H, J ) 1.6 Hz), 7.14 (m, 5H), 5.2 (s, 1H), 4.96 (s, 1H), 2.43 (t,
2H, J ) 7.7 Hz), 2.31 (dt, 2H, J ) 7.3, 1.6 Hz), 1.66 (m, 2H, J )
7.4 Hz). 13C NMR (CDCl3, 75 MHz) δ 202.2, 147.5, 140.8, 128.4,
127.5, 126.1, 113.1, 43.1, 34.6, 20.6. IR (neat) 1720 cm-1
.
DMSO (7 mL) was added to NaH (0.17 g of a 60% suspension
in mineral oil, 4.16 mmol, washed with hexanes) and the mixture
was stirred at 75 °C for 30 min. THF (10 mL) was added and the
reaction was cooled to -10 °C. Trimethylsulfonium iodide (0.85
g, 4.16 mmol) in DMSO (4 mL) was added dropwise to the reaction
over 10 min with the temperature of the reaction maintained at -5
°C during the addition. The aldehyde (0.613 g, 3.51 mmol) in THF
(3 mL) was then added to the ylide solution over 5 min. The reaction
was warmed to room temperature and stirred for 2 h. Water (25
mL) was added and the aqueous layer was extracted with EtOAc
(3 × 25 mL). The combined organic layers were washed with brine,
dried (MgSO4), concentrated, and chromatographed (20% EtOAc
in hexanes) to provide 430 mg (65%) of epoxide 12 as a clear oil:
1H NMR (CDCl3, 300 MHz) δ 7.27 (m, 5H), 5.30 (s, 1H), 5.09 (s,
1H), 2.90 (m, 1H), 2.73 (t, 1H, J ) 4.0 Hz), 2.57 (m, 2H), 2.45
(m, 1H), 1.55 (m, 4H). 13C NMR (CDCl3, 75 MHz) δ 128.3, 127.5,
126.1, 112.6, 52.1, 46.9, 35.3, 32.0, 24.6. HRMS calcd for C13H16O
188.1201, found 188.1199.
1-Azido-6-phenylhept-6-en-2-ol (18). A mixture of epoxide 12
(1 g, 5.32 mmol), NaN3 (3.4 g, 53.24 mmol), and NH4Cl (0.57 g,
10.65 mmol) in MeOH (12 mL) and water (1.5 mL) was heated in
a microwave for 10 min at 120 °C (0-300 W, 2.45 GHz microwave
(Biotage Initiator), 10-20 mL vial size, 2-5 deg/min). The reaction
mixture was cooled to room temperature, diluted with water (25
mL), and extracted with EtOAc (3 × 25 mL). The combined organic
layers were washed with brine, dried (MgSO4), concentrated, and
chromatographed (15% EtOAc in hexanes) to provide 1.13 g (93%)
of azido alcohol 18 as a clear oil: 1H NMR (CDCl3, 300 MHz) δ
7.28 (m, 5H), 5.31 (s, 1H), 5.09 (s, 1H), 3.73 (m, 1H), 3.20 (m,
2H), 2.5 (m, 2H), 1.98 (d, 1H, J ) 4.6 Hz), 1.51 (m, 3H). 13C
NMR (CDCl3, 75 MHz) δ 145.5, 138.5, 125.9, 124.9, 123.7, 110.3,
68.2, 54.6, 32.6, 31.3, 21.5. IR (neat) 3400, 2100 cm-1. HRMS
calcd for C13H17N3O‚Na+ 254.1269, found 254.1271.
2-(4-Phenylpent-4-enyl)aziridine (5b). To a solution of azido
alcohol 18 (0.7 g, 3.02 mmol) in dry acetonitrile (15 mL) was added
Ph3P (0.95 g, 3.6 mmol) and the reaction was heated to reflux for
1.5 h. The reaction mixture was cooled to room temperature,
concentrated, and chromatographed (5% MeOH in CH2Cl2) to
1466 J. Org. Chem., Vol. 73, No. 4, 2008

A Synthesis of 6-Azabicyclo[3.2.1]octanes
stirred for 2 h. The reaction was diluted with CH2Cl2, washed with
saturated aq Na2CO3 and brine, dried (MgSO4), concentrated, and
chromatographed (10% EtOAc in hexanes) to provide 0.285 g
(95%) of 7c as a clear oil: 1H NMR (CDCl3, 300 MHz) δ 8.02 (d,
2H, J ) 8.9 Hz), 7.34 (d, 2H, J ) 8.9 Hz), 7.05 (m, 5H), 3.92 (d,
1H, J ) 9.0 Hz), 3.56 (m, 1H), 2.79 (m, 1H), 2.43 (m, 1H), 2.20
(m, 1H), 1.71 (m, 6H). 13C NMR (CDCl3, 75 MHz) δ 147.5, 145.8,
139.5, 126.1, 125.8, 125.6, 125.0, 121.8, 68.6, 53.2, 48.3, 32.7,
32.1, 23, 17.9. HRMS calculated for C19H20N2O4S‚Na+ 395.1041
found 395.1058.
5-Phenyl-6-azabicyclo[3.2.1]octane (7b). PhSH (30 mg, 0.20
mmol) was added to a suspension of 7c (20 mg, 0.053 mmol) and
K2CO3 (30 mg, 0.212 mmol) in CH3CN:DMSO (49:1) (1 mL) at
room temparature. The reaction was heated to 50 °C and stirred
for 2 h. The reaction was diluted with saturated aqueous NH4Cl
solution and extracted with CH2Cl2 (3 × 5 mL). The combined
organic layers were washed with brine, dried (MgSO4), concen-
trated, and chromatographed (10% MeOH in CH2Cl2) to provide 7
mg (70%) of 7b as a clear oil: 1H NMR (CDCl3, 300 MHz) δ
7.04 (m, 5H), 3.01 (dd, 1H, J ) 5.76 and 4.5 Hz), 2.83 (d, 1H, J
) 10.29 Hz), 2.34 (m, 1H), 1.48 (m, 8H). 13C NMR (CDCl3, 75
MHz) δ 148.4, 128.23, 126.4, 125.5, 65.5, 51.5, 43.8, 41.7, 36.1,
30.6, 29.7, 20.3. HRMS calcd for C13H17N‚H+ 188.1439 found
188.1434.
Acknowledgment. This work was supported in part by the
National Science Foundation (CHE 9816208) and the National
Institutes of Health (DA013939). We also thank Ohio University
for support through the NanoBioTechnology Initiative.
Supporting Information Available: 1H and 13C NMR for
compounds 5b, 5c, 5d, 7b, 7c, 12, 16, 17, 18, 19b, and 19d/20d
and COSY spectra for 7b, 7c, and 19b. This material is available
free of charge via the Internet at http://pubs.acs.org.
JO702444C
J. Org. Chem, Vol. 73, No. 4, 2008 1467