5(6)-anti-substituted-2-azabicyclo[2.1.1]hexanes: A nucleophilic displacement route

Article abstract of DOI:10.1021/jo901725k

(Chemical Equation Presented) Nucleophilic displacements of 5(6)-anti-bromo substituents in 2-azabicyclo[2.1.1]hexanes (methanopyrrolidines) have been accomplished. These displacements have produced 5-anti-X-6-anti-Y- difunctionalized-2-azabicyclo[2.1.1]h

Full text of DOI:10.1021/jo901725k

pubs.acs.org/joc
5
(6)-anti-Substituted-2-azabicyclo[2.1.1]hexanes: A Nucleophilic
Displacement Route
,
Grant R. Krow,* Ram Edupuganti, Deepa Gandla, Amit Choudhary, Guoliang Lin,
†
†
†
‡
†
†
Philip E. Sonnet, Charles DeBrosse, Charles W. Ross III, Kevin C. Cannon, and
†
^
§
Ronald T. Raines
†
‡
Department of Chemistry, Temple University, Philadelphia, Pennsylvania 19122, Graduate Program in
§
Biophysics and Departments of Biochemistry and Chemistry, University of Wisconsin, Madison, Wisconsin
^
53706, Department of Chemistry, Penn State Abington, Abington, Pennsylvania 19104, and Department of
Medicinal Chemistry, Merck Research Laboratories, Merck & Co., Inc., West Point, Pennsylvania 19486
grkrow@temple.edu
Received August 13, 2009
Nucleophilic displacements of 5(6)-anti-bromo substituents in 2-azabicyclo[2.1.1]hexanes (methano-
pyrrolidines) have been accomplished. These displacements have produced 5-anti-X-6-anti-
Y-difunctionalized-2-azabicyclo[2.1.1]hexanes containing bromo, fluoro, acetoxy, hydroxy, azido,
imidazole, thiophenyl, and iodo substituents. Such displacements of anti-bromide ions require an
amine nitrogen and are a function of the solvent and the choice of metal salt. Reaction rates were
faster and product yields were higher in DMSO when compared to DMF and with CsOAc compared
to NaOAc. Sodium or lithium salts gave products, except with NaF, where silver fluoride in
nitromethane was best for substitution by fluoride. The presence of electron-withdrawing F, OAc,
N , Br, or SPh substituents in the 6-anti-position slows bromide displacements at the 5-anti-position.
3
5
-7
Introduction
Pyrrolidines 1, especially those with hydroxy, amino,
fluoro, or thio substituents in a 1,2-relationship β to the
nitrogen atom, are a valuable source of biologically signifi-
cant molecules. One strategy in the search for new bioactive
molecules is to incorporate key pharmacophoric units into
inflexible structures.
Viewed in this light, methano-
bridged pyrrolidines 2 (2-azabicyclo[2.1.1]hexanes) that dis-
play their functionalities in defined spatial orientations are of
interest. Such molecules may prove to be valuable scaffolds
for incorporation into proteins, for drug discovery, or for
3b
other purposes. To realize this potential there is a need for
1
2
3
4
8
practical methods to introduce a diverse array of heteroatom
9
substituents onto these structures.
(
1) (a) For a review of nonproteinogenic amino acids from 4-hydroxypro-
line, see: Remuzon, P . Tetrahedron 1996, 52, 13803. (b) For examples of the
utility of 4-hydroxyprolines, see also: Krow, G. R.; Lin, G.; Yu, F. J. Org.
Chem. 2005, 70, 590. References 2-12. Trabocchi, A.; Rolla, M.; Menchi, G.;
Guarno, A. Tetrahedron Lett. 2005, 46, 7813.
(2) For a recent example, see : (a) Deppermann, N.; Prenzel, A. H. G. P.;
Beitat, A.; Maison, W. J. Org. Chem. 2009, 74, 4267. (b) Zanardi, F.;
Burreddu, P.; Rassu, G.; Auzzas, L.; Battistini, L.; Curti, C.; Sartori, A.;
Nicastro, G.; Menchi, G.; Cini, N.; Bottonocetti, A.; Raspanti, S.; Casiraghi,
G. J. Med. Chem. 2008, 51, 1771. For further references, see: (c) Krow, G. R.;
Huang, Q.; Lin, G.; Centafont, R. A.; Thomas, A. M.; Gandla, D.;
DeBrosse, C.; Carroll, P. J. J. Org. Chem. 2006, 71, 2090,especially refs
1
-6.
3) For fluoropyrrolidines, see: (a) Giardina, G.; Dondio, G.; Grugni, M.
(
Synlett. 1995, 43, 55. (b) For leading references to 4-fluoroprolines and 5-
fluoromethanoproline, see: Jenkins, C. L.; Lin, G.; Duo, J.; Rapolu, D.;
Guzei, I. A.; Raines, R. T.; Krow, G. R. J. Org. Chem. 2004, 69, 8565.
Heteroatoms at C (C ) of N-acyl-2-azabicyclo[2.1.1]hexanes
5
have been introduced by rearrangement routes (X = syn- or
6
8
232 J. Org. Chem. 2009, 74, 8232–8242
Published on Web 10/02/2009
DOI: 10.1021/jo901725k
r 2009 American Chemical Society

Krow et al.
anti-halogen, hydroxyl), nucleophilic ring closure of cyclo-
JOCArticle
1
0
5-anti-amines, isolated as their carbamates 2b [R = H,
X = NHCOOBn(Et)]. The major 5-syn-carboxylic acid 2e
has been used to introduce other 5-heteroatoms by radical
decarboxylative substitutions of either the acid or its Barton
ester. Reactions led to mainly 5-syn-chloro, 5-syn-bromo,
5-syn-iodo, and 5-syn-pyridylthioether substitution products
admixed with only minor amounts of the 5-anti isomers
(0-11%); an exception was the iodide, which gave
17-44% 5-anti-isomer. Yields were generally poor, and this
nonstereospecific method is not of general utility as a source
of halide or thioether substitution. The rearrangement route
remains the most useful for introduction of 5-anti-hydroxy
and 5-anti-bromine groups as in 2a and 2e. Thus, methods
to displace these substituents by other nucleophiles are
welcome.
6a
butanes (X=syn-SePh), or a thermal 2 + 2 cycloaddition (X/
1
1
H=difluoride). There are a few examples of N-acyl mono-
heteroatom-substituted anti-5-hydroxy-2-azabicyclo[2.1.1]-
hexanes 2a (X=OH) formed by reductive dehalogenation of
3
b,10a,10d
5
-anti,6-anti-bromohydrins.
Recently, we described the preparation of N-BOC-5-syn-
and 5-anti-carboxy-2-azabicyclo[2.1.1]hexanes 2e (R = H,
1
2
X=COOH), isolated mainly as the syn-5-carboxy isomers,
and their use for introduction of heteroatom functionality
into this ring system. The Curtius rearrangement was
especially useful for the stereospecific conversion of
2
c
5
-syn- and 5-anti-acids to the corresponding 5-syn- and
(
4) For 4-thioprolines, see: (a) Williams, J. M.; Brands, K. M. J.; Skerlj,
R. T.; Jobson, R. B.; Marchesini, G.; Conrad, K. M.; Pipik, B.; Savary, K. A.;
Tsay, F.-R.; Houghton, P. G.; Sidler, D. R.; Dolling, U.-H.; DiMichele,
L. M.; Novak, T. J. J. Org. Chem. 2005, 70, 7479. (b) Azami, H.; Barrett, D.;
Tanaka, A.; Sasaki, H.; Matsuda, K.; Chiba, T.; Matsumoto, Y.Matsumoto,
S.; Morinaga, C.; Ishiguro, K.; Tawara, S.; Sakane, K.; Takasugi, H. Bioorg.
Med. Chem. Lett. 1995, 5, 2199. (c) Kemp, D. S.; Curran, T. P.; Davis, W. M.;
Boyd, J. G.; Muendel, C. J. Org. Chem. 1991, 56, 6672. For a 4-thiopyrro-
lidine, see: (d) Shibata, T.; Iono, K.; Sugimura, Y. Heterocycles 1986, 24,
Nucleophilic substitution reactions of 5-tosylbicyclo-
[2.1.1]hexanes, the parent carbon bicycle of structures 2,
provide insights into the reactivity of 5-substituents in this
strained ring system. The substitution reactions of 5-syn-
substituents occur fairly easily and proceed with retention of
configuration but are accompanied by rearrangement pro-
ducts. The syn-5-alcohol 3a and phosphorus tribromide
afforded a product assigned as the 5-syn-bromide 3b (17%)
admixed with some 4-bromocyclohexene, while syn-5-tosy-
late 3c reacts with tetrabutylammonium chloride at 5 ꢀC for
1
331.
5) For leading references with bridged pyrrolidines, see: (a) Bunch, L.;
(
Liljefors, T.; Greenwood, J. R.; Frydenvang, K.; Brauner-Osborne, H.;
Krogsgaard-Larsen, P.; Madsen, U. J. Org. Chem. 2003, 68, 1489. (b) Hart,
B. P.; Rapoport, H. J. Org. Chem. 1999, 64, 2050. (c) Han, W.; Pelletier, J. C.;
Mersinger, L.; Ketner, C. A.; Hodge, C. N. Org. Lett. 1999, 1, 1875.
(6) For biologically interesting 2-azabicyclo[2.1.1]hexanes, see: (a) Lescop,
2
9 h to afford a product assigned as 5-syn-chloro[2.1.1]-
C.; Mevellec, L.; Huet, F. J. Org. Chem. 2001, 66, 4187. (b) Piotroski, D. W.
Synlett. 1999, 1091. (c) Esslinger, C. S.; Koch, H. P.; Kavanaugh, M. P.; Philips,
D. P.; Chamberlin, A. R.; Thompson, C. M.; Bridges, R. J. Bioorg. Med. Chem.
Lett. 1998, 8, 3101. (d) Koch, H. P.; Kavanaugh, M. P.; Esslinger, C. S.;
Zerangue, N.; Humphrey, J. M.; Amara, S. G.; Chamberlain, A. R.; Bridges,
R. J. Mol. Pharmacol. 1999, 56, 1095. (e) Mapelli, C.;van Halbeek, H.; Stammer,
C. H. Biopolymers 1990, 29, 407. (f) Bell, E. A.; Qureshi, M. Y.; Pryce, R. J.;
Janzen, D. H.; Lemke, P.; Clardy, J. J. Am. Chem. Soc. 1980, 102, 1409. (g) Park,
T. H.; Ha, Y. H.; Jeong, D. Y. Patent Application WO 98-KR246 19989898;
Chem. Abstr. 1999, 130, 182388. (h) Pirrung, M. C. Tetrahedron Lett. 1980, 21,
1
hexane 3d (43%) with retained stereochemistry. Both of
3a
these products are suggestive of neighboring group
13b
participation by the neighboring methanobridge. On the
other hand, nucleophilic displacement of 5-anti-substituents,
our goal, is more difficult. The syn-tosylate 3c reacted at a
6
13b,c
rate 3 ꢀ 10 time that of the 5-anti-tosylate 4.
To
induce a reasonable rate for acetic acid solvolysis of the
anti-tosylate 4, a temperature of 164 ꢀC was required. More
importantly, none of the products retained the bicyclo-
4
577. (i) Hughes, P.; Martin, M.; Clardy, J. Tetrahedron Lett. 1980, 21, 4579. ( j)
Kite, G. C.; Ireland, H. Phytochemistry 2002, 59, 163. (k) Juvvadi, P.; Dooley, D.
J.; Humblet, C. C.; Lu, G. H.; Lunney, E. A.; Panek, R. L.; Skeean, R.; Marshall, G.
R. Int. J. Peptide Protein Res. 1992, 40, 163. (l) Piela, L.; Nemethy, G.; Scheraga,
H. A. J. Am. Chem. Soc. 1987, 109, 4477. (m) Montelione, G. T.; Hughes, P.;
Clardy, J.; Scheraga, H. A. J. Am. Chem. Soc. 1986, 108, 6765. (n) Talluri, S.;
Montelione, B. T.; van Duyne, G.; Piola, L.; Clardy, J.; Scheraga, H. A. J. Am.
Chem. Soc. 1987, 109, 4473. (o) Gaoni, Y. Org. Prep. Proced. Int. 1995, 27, 185.
[
2.1.1]hexane structure. Acetolysis of 4 produced 4-cyclo-
hexenyl tosylate (80%), 4-cyclohexenyl acetate (8%),
and bicyclo[3.1.0]hex-2-yl acetate (8%) as the major
13c
products.
(p) Gaoni, Y.; Chapman, A. G.; Parvez, N.; Pook, P. C.-K.; Jane, D. E. J. Med.
Chem. 1994, 37, 4288. (q) Rammeloo, T.; Stevens, C. V.; De Kimpe, N. J. Org.
Chem. 2002, 67, 6509. (r) Rammeloo, T.; Stevens, C. V.; De Kimpe, N. J. Chem.
Soc., Chem. Commun. 2002, 250. (s) Malpass, J. R.; Patal, A. B.; Davies, J. W.;
Fulford, S. Y. J. Org. Chem. 2003, 68, 9348. (t) Stevens, C. V.; Smagghe, G.;
Rammeloo, T.; De Kimpe, N. J. Agric. Food Chem. 2005, 53, 1945. (u) Patel,
A. B.; Malpass, J. R. J. Med. Chem. 2008, 51, 7005.
3
b
(
7) For 5(6)-substituted methanoprolines, see ref and (a) Krow, G. R.;
Lin, G.; Fang, Y. J. Org. Chem. 2005, 70, 590. (b) Krow, G. R.; Lin, G.;
Rapolu, D.; Fang, Y.; Lester, W. S.; Herzon, S. B.; Sonnet, P. E. J. Org.
Chem. 2003, 68, 5292.
(
8) Kim, W.; George, A.; Evans, M.; Conticello, V. P. ChemBioChem.
004, 5, 928.
9) For a review of synthetic approaches to 2-azabicyclo[2.1.1]hexanes,
see: Krow, G. R.; Cannon, K. C. Heterocycles 2004, 62, 877.
10) For 3-alkyl(aryl),5(6)-heteroatom-substituted methanopyrrolidines,
see : (a) Krow, G. R.; Lin, G.; Yu, F. J. Org. Chem. 2005, 70, 590. (b) Krow,
G. R.; Yuan, J.; Lin, G.; Sonnet, P. E. Org. Lett. 2002, 4, 1259. (c) Krow,
G. R.; Lee, Y. B.; Lester, W. S.; Liu, N.; Yuan, J.; Duo, J.; Herzon, S. B.;
Nguyen, Y.; Zacharias, D. J. Org. Chem. 2001, 66, 1805. (d) Krow, G. R.;
Lester, W. S.; Liu, N.; Yuan, J.; Hiller, A.; Duo, J.; Herzon, S. B.; Nguyen,
Y.; Cannon, K. J. Org. Chem. 2001, 66, 1811. For other 5(6)-heteroatom
substituted methanopyrrolidines, see: (e) Krow, G. R.; Lee, Y. B.; Lester,
W. S.; Christian, H.; Shaw, D. A.; Yuan, J. J. Org. Chem. 1998, 63, 8558. (f )
Krow, G. R.; Lin, G.; Moore, K. P.; Thomas, A. M. C.; DeBrosse, C.; Ross,
C. W. III; Ramjit, H. G. Org. Lett. 2004, 6, 1669. (g) Krow, G. R.; Lin, G.;
Yu, F.; Sonnet, P. E. Org. Lett. 2003, 5, 2739.
2
(
Nevertheless, there are two examples of nucleophilic dis-
placement reactions of 5-anti-substituents in N-acyl-2-
azabicyclo[2.1.1]hexanes by fluoride in which products have
been isolated that maintain the integrity of the heterobi-
cyclic structure. The conversion of alcohol 5a to fluoride 6a
was carried out using bis(2-methoxyethyl)aminosulfur tri-
fluoride [BAST or Deoxo-Fluor] in refluxing methylene
(
3
b
chloride (63%) (eq 1). Limited success was observed with
the replacement of the 5-anti-iodo substituent of 5b by
fluoride using AgF/nitromethane at 80 ꢀC/4 h to give 6b
(
11) Amii, H.; Ichihara, Y.; Nakagawa, T.; Kobayashi, T.; Uneyama, K.
J. Chem. Soc., Chem. Commun. 2003, 2902.
12) (a) Krow, G. R.; Lin, G.; Herzon, S. B.; Thomas, A. M.; Moore,
2
c
(
19%) (eq 2). Retention of stereochemistry was observed in
(
both cases of displacement reactions of C -anti-substituents.
5
We have not been successful in nucleophilic displacements of
K. P.; Huang, Q.; Carroll, P. J. J. Org. Chem. 2003, 68, 7562. (b) Kwak, Y.-S.;
Winkler, J. D. J. Am. Chem. Soc. 2001, 123, 7429.
J. Org. Chem. Vol. 74, No. 21, 2009 8233

Krow et al.
JOCArticle
5-anti-bromo substituents in N-acyl-5-anti-bromo-2-azabi-
cyclo[2.1.1]hexanes (see Supporting Information).
SCHEME 1. Synthesis of N-Benzylbromides
SCHEME 2. Reactions of Dibromide 9
It occurred to us that replacement of the N-acyl substitu-
ent by an N-alkyl group might facilitate nucleophilic sub-
1
4
stitution reactions. Malpass and White have shown that a
free amine can facilitate displacements in a normally slow-
1
3
reacting 7-norbornyl position. The 7-bromo group in
N-benzyl-anti-7-bromo-2-azabicyclo[2.2.1]heptane was
7
displaced by various nucleophiles at 100-110 ꢀC in DMF
to give products 8. Only products with retained stereochem-
istry were observed, presumably the result of neighboring
1
4
group participation.
7
2 (Scheme 1). The known dibromide 13 was selectively
b
7b
1
monodebrominated using (TMS) SiH/toluene/70 ꢀC to give
3
monobromide 14 (74%). Conversion of alkene 12 to bromo-
fluoride 15 (53%) was carried out using NBS/nitromethane/
1
7
Et N 3HF. Hydrogenolysis of the carbobenzyloxy pro-
3
3
tecting groups of 13-15 with H /Pd(OH) /MeOH and sub-
sequent benzylation with benzyl bromide/Et N/CH CN
3 3
2
2
The key objective of this work was to see if replacement of
N-acyl groups by N-benzyl in readily available 5-anti-bro-
mo- and 5-anti-,6-anti-dibromo-2-azabicyclo[2.1.1]hexanes
would allow for displacement of the bromine atom by useful
afforded the N-benzyl compounds 9-11 in 51-69% overall
yields for the two steps.
Our first attempts to effect nucleophilic displacements of
dibromide 9 (Scheme 2) were carried out in DMF under
1
5
heteroatom nucleophiles. Specifically, dibromide 9, mono-
bromide 10, and fluorobromide 11 have been chosen as
substrates. We now describe conditions that enable prepara-
tion of 5(6)-anti-substituted-2-azabicyclo[2.1.1]hexanes with
halogen-, nitrogen-, sulfur-, and oxygen-containing groups
X starting from these bromides. Since preparation of 5-anti-
bromides with compatible substituents at other ring posi-
1
4
conditions used successfully by Malpass for halide displace-
ments with bromide 5 (R=Bn, Y=H). The results are shown
in Table 1. Dibromide 9 was slowly converted to its diacetate
1
8
16a using excess cesium acetate (entry 1), but displacement
of the second bromine was difficult. Even after 5 days there
was unreacted starting material and a large amount of bro-
moacetate 17 in the reaction mixture. For the stereochemical
3
b,9,10
tions is feasible,
the functional group modifications
described for these bromides should prove useful in the
preparation of more highly functionalized 5(6)-substituted-
assignment of diacetate 16, the protons H /H are identical
5 6
1
and appear as a singlet in the H NMR spectrum. The retained
2
precursors of methanoprolines 2 (R = COOH);
-azabicyclo[2.1.1]hexanes 2. Some of these structures can be
3
5-anti,6-anti stereochemistry is apparent from the absence of
coupling between H or H and their vicinal syn protons H /
1 4 5
b,16
we
especially desired to prepare novel 5,6-dihydroxy-, 5,6-di-
fluoro-, 5,6-diamino-, and mixed 5,6-hydroxyfluorides that
are not available by other synthetic routes.
H
6
. In this ring system these syn protons characteristically do
2
c
not show vicinal coupling. For bromoacetate 18, there is the
characteristic W-plan coupling between the syn protons H
7
b
5
7
and H (J = 7.2 Hz). Methanolysis of the diacetate 16a
b
6
Results and Discussion
afforded diol 16b. Attempted preparation of difluoride 18
from dibromide 9 using AgF/DMF formed instead the pyr-
19
role aldehyde 19 (entry 2).
The requisite N-benzyl dibromides 9-11 were prepared
from the N-alkoxycarbonyl dihydropyridine photoproduct
To introduce nitrogen functionality, bromide 9 was re-
acted with sodium azide in DMF (entry 3) to give diazide 20
and azidobromide 21. As noted with CsOAc (entry 1), it was
difficult to replace the second bromine in azidobromide 21
despite extended reaction times (8 days). The symmetrical
diazide 20 gave a singlet for H /H , while bromoazide 21
(
13) (a) Wiberg, K. B.; Lowry, B. R.; Colby, T. H. J. Am. Chem. Soc.
1
1
961, 83, 3998. (b) McDonald, R. N.; Reineke, C. E. J. Org. Chem. 1967, 32,
878. (c) Wiberg, K. B.; Fenoglio, R. Tetrahedron Lett. 1963, 4, 1273.
(
14) (a) Malpass, J. R.; White, R. J. Org. Chem. 2004, 69, 5328. (b)
Malpass, J. R.; Handa, S.; White, R. Org. Lett. 2005, 7, 2759.
15) We did not expect to isolate aziridinium ion salts. Aziridinium salts
are preferred for 6-anti-bromo-2-azabicyclo[2.2.1]heptanes, although not the
(
5
6
14a
7
-anti-isomers. See ref
and (a) Sosonyuk, S. E.; Bulanov, M. N.;
Leshcheva, I. F.; Zyk, N. V. Russ. Chem. Bull. 2002, 51, 1254. (b) Bulanov,
M. N.; Sosonyuk, S. E.; Zyk, N. V.; Zefirov, N. S. Russ. J. Org. Chem. 2003,
(17) Shellhamer, D. F.; Horney, M. J.; Pettus, B. J.; Pettus, T. L.; Stringer,
J. M.; Heasley, V. L. J. Org. Chem. 1999, 64, 1094.
(18) Sakagami, H.; Ogasawara, K. Synlett 2001, 1, 45.
(19) Downie, I. M.; Earle, M. J.; Heaney, H.; Shuhaibar, K. F. Tetra-
hedron 1993, 49, 4015.
3
9, 415.
(16) Krow, G. R.; Herzon, S. B.; Lin, G.; Qiu, F.; Sonnet, P. E. Org. Lett.
2
002, 4, 3151.
8
234 J. Org. Chem. Vol. 74, No. 21, 2009

Krow et al.
JOCArticle
TABLE 1. Nucleophilic Substitutions of Dibromide 9
yield
(%)
entry substrate reagent
conditions
product
X
Y
a
16a OAc OAc 40
1
9
CsOAc DMF/60 ꢀC/5 d
1
19
20
7
Br OAc 42
72
2
3
9
9
AgF
NaN
DMF/50 ꢀC/8 h
DMF/60 ꢀC/8 d
3
N
3
N
N
3
3
34
49
1
b
FIGURE 1. H NMR spectrum (400 MHz) for H
difluoride 18 (CDCl ).
5 6
/H protons in
2
1
Br
3
4
5
9
9
CsOAc DMSO/60 ꢀC/5 d
NaOAc DMSO/60 ꢀC/5 d
16a OAc OAc 89c
16a OAc OAc 14
17
19
Br OAc 59
22
SCHEME 3. Reactions of Monobromides 10
d
6
7
9
16b
NaF
BAST CH
DMSO/70 ꢀC/5 d
2
Cl
2
/25 ꢀC/12 h 18
F
F
24
40
52
1
9
8
9
AgF
CH
h
3
NO
2
/50 ꢀC/8 18
F
F
1
20
22
9
24
87
37
29
9
1
9
9
NaN
3
DMSO/60 ꢀC/2d
N
3
N
3
0
NaSPh DMSO/60 ꢀC/5 h
SPh SPh
Br SPh
c
2
3
a
b
Also 10% dibromide 9. Also 17% of dibromide 9. Also 15%
d
dibromide 9. Also 50% dibromide 9.
showed the characteristic W-plan coupling for H /H indica-
6
5
ting that both structures have 5-anti,6-anti stereochemistry.
The long reaction times and low yields in DMF solvent for
preparation of desired diacetate 16a and diazide 20, along
with the failure to prepare the desired difluoro isomer 18,
initiated a search for alternative superior reaction conditions.
Dimethylsulfoxide was found to be a superior solvent for
nucleophilic displacement reactions of dibromide 9 (entry
Reactions of Monobromides 10 and 11. We next turned our
attention to the monobromide 10 (Scheme 3). Its substitution
reactions are tabulated in Table 2. Our initial efforts again
focused upon reactions in DMF solvent because of prece-
1
4
dent. With silver acetate in DMF bromide 10 gave acetate
4a in moderate yield (entry 1). This was methanolyzed using
CO /methanol to give alcohol 24b (84%). To show that
2
2
0
K
2
3
4
). The substitution of DMSO for DMF, and otherwise the
the benzyl group could be removed without destruction of
the strained ring, alcohol 24 was hydrogenolyzed and the
resulting amine was protected by reaction with (BOC) O to
2
same reaction conditions in entry 1 for the reaction with
CsOAc, resulted in complete conversion to the diacetate 16a
in a suitable yield after 5 days. The use of cesium acetate was
clearly superior to sodium acetate in this reaction (entry 5).
Our pleasure was tempered somewhat by the failure of
DMSO as solvent to enable dibromide 9 to be converted to
a desired difluoride 18 in the presence of NaF (entry 6); again
only the pyrrole aldehyde 19 was obtained. However, it was
discovered that difluoride 18 could be obtained in small yield
give N-BOC alcohol 25 (92%).
Monobromide 10 and AgF in DMF gave the same ring-
opened and oxidized pyrrole aldehyde 19 (entry 2) observed
upon reaction of dibromide 9 under these conditions. Bro-
mide 10 in DMF did not react with NaF (entry 3) but did
react with NaN and gave azide 27 in moderate yield (entry
3
3
b
4). The azide 27 was reduced using triphenylphosphine/
water, and the resultant amine was reacted with (BOC) O
(24%) by reaction of diol 16b with BAST (entry 7). The
symmetrical difluoride evidenced the expected multiplet
2
1
to afford the protected carbamate 28. An N-imidazole ring
could be introduced by generation of lithium imidazole in
DMF and reaction with bromide 10 to give amine 29 (entry
5). Sodium iodide (3 equiv) effected partial displacement of
bromide ion to give an inseparable 50:50 mixture of bromide
0
0
AA XX pattern in the H NMR spectrum shown in Figure 1.
The main product in the reaction was the oxidized ring-
cleaved pyrrole aldehyde 19. Later, it was found that the
difluoride 18 could be made directly from the dibromide 9 in
better yield by reaction with silver fluoride in nitromethane
as solvent (entry 8).
1
0 and iodide 31 (entry 6).
DMSO again proved to be a superior solvent for the
The symmetrical diazide 20 also was prepared from di-
bromide 9 in both vastly improved yield (87%) and in shorter
time (2 days) simply by replacing DMF with DMSO solvent
replacement of bromide using cesium acetate (entry 7), and
bromide 10 produced acetate 24a in high yield. Cesium
acetate was found to be a better salt for the displacement
than NaOAc. NaF in DMSO did not yield a fluoride with
bromide 10 (entry 8). The desired fluoride 26 could be
obtained from alcohol 24b upon reaction with BAST
(entry 9). With DMSO solvent it was also possible to prepare
the symmetrical thiophenyl ether 22, although after 5 h
some bromothiophenyl ether 23 and unreacted dibromide
9
remained (entry 10).
(entry 9), but the fluoride 26 was obtained in higher yield
from bromide 10 using AgF in nitromethane (entry 10).
DMSO was shown to be a better solvent for bromide 10 in
(20) (a) Creary, X.; Burtch, E. A.; Jiang, Z. J. Org. Chem. 2003, 68, 1117.
b) Creary, X.; Burtch, E. A. J. Org. Chem. 2004, 69, 1227.
(
J. Org. Chem. Vol. 74, No. 21, 2009 8235

Krow et al.
JOCArticle
TABLE 2. Nucleophilic Substitutions of Bromide 10
SCHEME 4. Reactions of Fluorobromide 11
yield
(%)
entry substrate reagent
conditions
product
X
1
2
3
4
5
6
7
8
9
1
1
1
1
10
10
10
10
10
10
10
10
24b
10
10
10
10
AgOAc DMF/60 ꢀC/12 h
24a
19
10
27
29
31
24a
10
26
26
27
30
31
OAc 54
a
AgF
NaF
NaN
DMF/70 ꢀC/24 h
DMF/70 ꢀC/12 h
DMF/70 ꢀC/12 h
DMF/70 ꢀC/8 d
DMF/70 ꢀC/3 d
42
88
51
55
Br
3
N
Nu
I
3
b
b
LiNu
NaI
c
d
50
TABLE 3. Nucleophilic Substitutions of Bromofluoride 11
e
CsOAc DMSO/70 ꢀC/6 h
NaF
DMSO/70 ꢀC/12 h
BAST CH Cl
/40 ꢀC/12 h
NO
/50 ꢀC/12 h
DMSO/70 ꢀC/5 h
OAc 90
Br
F
F
82
62
80
88
77
2
2
0
1
2
3
AgF
CH
3
2
NaN
3
N
3
NaSPh DMSO/60 ꢀC/5 h
SPh
I
f
g
NaI
acetone/reflux/4 d
74
entry substrate reagent
conditions
product
X
yield (%)
a
a
Bromide 10 was stable in DMF/70 ꢀC/12 h; 90% recovery, no 19
formed. Nu = N-imidazole. 3 equiv. Admixed with unreacted
b
c
d
1
2
3
4
5
6
7
11
11
11
11
11
11
11
CsOAc DMF/70 ꢀC/5 d
32a
34
32a
32a
34
OAc
N3
30
43
b
e
bromide 10. To separate samples of the monobromide 10 in
NaN3
DMF/70 ꢀC/5 d
c
33
NaOAc DMSO/70 ꢀC/5 d
CsOAc DMSO/70 ꢀC/5 d
OAc
OAc
DMSO-d
6
was added 1.5 equiv of either NaOAc (sample A) or CsOAc
90
67
(sample B). After 6 h the conversion to acetate 24a was 39% for sample
A and 66% for sample B by NMR analysis. 20 equiv. Total conver-
sion of 10.
f
g
NaN3
DMSO/70 ꢀC/7 d
N3
d
NaSPh DMSO/60 ꢀC/5 h
37
37
SPh
SPh
15
69
e
NaSPh DMSO/60 ꢀC/9 d
its reactions with NaN to give the azide 27 (entry 11) or with
3
NaSPh to give the thiophenyl ether 30 (entry 12). It was
possible to convert the bromide 10 to the iodide 31 using
a
b
Also 64% unreacted 11. Also 31% unreacted 11. Also 64%
c
d
unreacted 11. Also 66% unreacted 11. Also 4% unreacted 11.
e
1
H
excess NaI/acetone after extended reflux (entry 13).
NMR indicated complete conversion of the bromide. The
-anti stereochemistry for all new compounds in Table 2 was
reaction of 11 with NaN in DMSO (entry 5). It was also
3
5
indicated by the observation of W-plan H NMR couplings
possible to prepare the fluorothioether 37 using NaSPh
in DMSO, although the reaction was quite slow (entries 6
and 7).
The ease of bromide displacements in bromides 9-11 was
dependent upon the adjacent substituent X. Monitoring of
the disappearance of starting bromides indicated a relative
reactivity order monobromide 10 > dibromide 9 > fluoro-
bromide 11 (see Supporting Information). Nucleophilic
substitution reactions with the bromide 10 in DMSO solvent
1
(
J5,6=6.9-7.6 Hz).
The next substrate investigated was the bromofluoride 11
Scheme 4), and its reactions are tabulated in Table 3. The
(
bromofluoride 11 reacted slowly with CsOAc in DMF to
give fluoroacetate 32a (entry 1). A sequence of methanolysis
of the acetate 32a to alcohol 32b and then hydrogenolysis
followed by acylation with (BOC) O gave a desired fluor-
2
oalcohol 33 (86%). Formation of azide 34 from bromofluor-
ide 11 was also a slow reaction (entry 2) and was
accompanied by decomposition. The azide 34 was converted
to the amine 35 using triphenylphosphine/water, and the
amine was acylated to give the acetamide 36.
with CsOAc or NaN required hours for completion, with
3
the dibromide 9 a few days, and with the fluorobromide 11
5
-7 days. In addition, upon displacement of one of the
bromides of dibromide 9 by acetate, azide, or thiophenyl it
took longer to displace the remaining bromides of bromoa-
cetate 17, bromoazide 21, or bromo(phenylthio) ether 23
While fluoroalcohol 32b showed coupling between OH-F
2
J=3.9 Hz), there was no evidence for such coupling in
1
(
(Table 1). These reactivity orders indicate that all parallel
either the fluorine or proton NMR spectra of amine 35 or
amide 36. Molecular models indicate the 5-anti- and 6-anti-
substituents are not actually parallel but point slightly away
from each other. The 5-anti,6-anti arrangement of halogen
heteroatom substituents in the adjacent methyl bridge, so far
investigated, are rate-retarding for bromide substitution.
One plausible explanation for the rate-retarding effects
of heteroatom groups is that electron withdrawal of the
nitrogen lone pair by a second atom X reduces the ability
for nitrogen atom interaction with the leaving bromide. In
molecular orbital terms the nitrogen’s lone pair of electrons
could interact with the σ* orbitals of the C-Br bond. On
the basis of the electronegativity of the non-reacting C-X
bond (H < Br < F), it might be predicted that the nfσ*
overlap for the reacting C-Br bond should follow the order
monobromide 10 > dibromide 9 > fluorobromide 11. To
gain evidence about the substituent effect upon lone pair
nfσ* interactions, NBO calculations were performed for
substituents was again indicated by W-plan couplings (J5,6
.1-7.8 Hz).
Replacement of solvent DMF by DMSO facilitated
=
7
the displacement reactions of 11 to give fluoroacetate 32a
with either NaOAc (entry 3) or more effectively with
CsOAc (entry 4). The same solvent effect was observed
in the improved yields in formation of azide 34 upon
(
21) Krow, G. R.; Gandla, D.; Guo, W.; Centafont; Lin, G.; DeBrosse,
C.; Sonnet, P. E.; Ross, C. W. III; Ramjit, H.; Cannon, K. C. J. Org. Chem.
008, 73, 2122.
2
8
236 J. Org. Chem. Vol. 74, No. 21, 2009

Krow et al.
JOCArticle
TABLE 4. Second-Order Perturbative Estimates (NBO Basis) for nfσ* Interaction Energies for Bromides 9-11
a
nfσ* (kcal/mol)
nfσ* (kcal/mol)
b
-X
entry
substrate
X
NfC
5
-Br
NfC
6
substrate
NfC
5
-Br
NfC
6
-X
c
1
2
3
a
9endo-N-Bn
10endo-N-Bn
11endo-N-Bn
Br
H
F
1.71
1.75
1.63
0.96
(0.28)
(0.69)
9 exo-N-Bn
10 exo-N-Bn
11 exo-N-Bn
0.96
0.89
0.92
1.71
(0.55)
(1.63)
22,23
Geometry optimizations, frequency calculations, and NBO analyses were performed at the B3LYP/6-311þG(2d,p) level of theory on 9-11.
b
c
Those bonds that do not have leaving groups for substitutions are in parentheses. The benzyl group has been arbitrarily assigned as endo (or exo) to
enable us to distinguish the two bromides as C and C for purposes of this analysis.
5
6
SCHEME 5. Calculated Ionic Intermediates for Reactions of N-
Methyl-azabicyclic Bromides 38-40
FIGURE 2. nfσ* Orbital overlaps for C-Br bonds in benzyl
dibromide 9.
2
2,23
structures 9-11.
The calculations, shown in Table 4,
indicate the nitrogen lone pair electrons, front lobe and rear
lobe, interact with the σ* orbitals of both C5 and C6
substituents. Pictures in Figure 2 show the orbital overlap
for the two lobes of the nitrogen lone pair orbital in the
23d
dibromide 9.
occurs from the endo-N-benzyl conformer with the rear lobe
The larger nfσ* interaction in each case
24
(
yellow) ofthe nitrogen atom overlapping (NfC Br). While
5
(
22) Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb,
it is true that the calculated relative overlap stabilization
energies (10 > 9 > 11) are consistent with the observed
reactivity order (10 > 9 > 11) with nucleophiles, the ground
state interaction energies are too similar for this factor alone
to explain the large relative rate differences. Indeed, the
relative stabilization energies may differ appreciably as the
corresponding transition state energies are approached. Elec-
tron lone pair orbital interactions would be expected to
become more important as positive charge is created at C5.
To gain information on charged intermediates derived
from N-methyl substrates 38a-c, we performed single point
energy calculations of N-methyl carbocations 39a-c
M. A.; Cheeseman, J. R.; Montgomery, Jr., J. A.; Vreven, T.; Kudin, K. N.;
Burant, J. C.; Millam, J. M.; Iyengar, S. S.; Tomasi, J.; Barone, V.; Mennucci,
B.; Cossi, M.; Scalmani, G.; Rega, N.; Petersson, G. A.; Nakatsuji, H.; Hada,
M.; Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.; Ishida, M.; Nakajima,
T.; Honda, Y.; Kitao, O.; Nakai, H.; Klene, M.; Li, X.; Knox, J. E.;
Hratchian, H. P.; Cross, J. B.; Bakken, V.; Adamo, C.; Jaramillo, J.;
Gomperts, R.; Stratmann, R. E.; Yazyev, O.; Austin, A. J.; Cammi, R.;
Pomelli, C.; Ochterski, J. W.; Ayala, P. Y.; Morokuma, K.; Voth, G. A.;
Salvador, P.; Dannenberg, J. J.; Zakrzewski, V. G.; Dapprich, S.; Daniels,
A. D.; Strain, M. C.; Farkas, O.; Malick, D. K.; Rabuck, A. D.; Ragha-
vachari, K.; Foresman, J. B.; Ortiz, J. V.; Cui, Q.; Baboul, A. G.; Clifford, S.;
Cioslowski, J.; Stefanov, B. B.; Liu, G.; Liashenko, A.; Piskorz, P.;
Komaromi, I.; Martin, R. L.; Fox, D. J.; Keith, T.; Al-Laham, M. A.; Peng,
C. Y.; Nanayakkara, A.; Challacombe, M.; Gill, P. M. W.; Johnson, B.;
Chen, W.; Wong, M. W.; Gonzalez, C.; Pople, J. A. Gaussian 03, Revision
C.02; Gaussian, Inc.: Wallingford CT, 2004.
(Scheme 5) by two different means: (1) Hartree-Fock 6-
(
23) (a) Weinhold, F. Natural Bond Orbital Methods. In Encyclopedia of
25 26
Computational Chemistry; Schleyer, P. v. R., Allinger, N. L., Clark, T., Gasteiger,
J., Kollman, P. A., Shaefer, H. F., III, Schreiner, P. R., Eds.; John Wiley & Sons:
Chichester, UK, 1998; Vol. 3, p 1792. (b) Glendening, E. D.; Badenhoop, J. K.;
Reed, A. E.; Carpenter, J. E.; Bohmann, J. A.; Morales, C. M.; Weinhold, F. NBO
31þG(d,p) and (2) B3LYP/6-31þG(d,p) methods/basis
22
sets using the Gaussian 03 suite of computations. We then
optimized these structures for geometry using the same two
methods. In all instances, save one, each optimization of a
cation 39 led to an iminium ion 40; exo and endo isomers led
to the same ions. The one exception occurred with bromo-
fluoride 38c using method 2 in which the aziridinium ion 41c
was the outcome of the calculation. Independently, we
optimized iminium ion 40c using method 2. The fluoro
aziridinium ion 41c was calculated to be 43.5 kcal/mol less
5
.0; 2001. (c) Weinhold, F.; Landis, C. R. Valency and Bonding: A Natural Bond
Orbital Donor-Acceptor Perspective; Cambridge University Press: Cambridge,
U.K., 2005. (d) Depictions of orbital overlap were generated using NBOview 1.1:
Wendt, M.; Weinhold, F. NBOView 1.1; Theoretical Chemistry Institute, Uni-
versity of Wisconsin, Madison: Madison, WI, 2001.
(
24) Crystals of dibromide 9 were subjected to X-ray analysis (see
Supporting Information). It was envisioned that an especially significant
and equal interaction of the nitrogen lone pair electrons with the C-Br σ*
orbitals might lead at the extreme to a symmetrical structure for dibromide 9
with a planar nitrogen atom. However, nitrogen is tetrahedral and the sum of
the bond angles including the nitrogen atom is 330.1ꢀ. The C-Br bond
˚
proximal to the N-benzyl group is 1.945 A, and the distal C-Br bond is 1.942
˚
A. While suggestive of an nfσ* interaction for the longer proximal bond
distance, these bond lengths are essentially identical within experimental
(25) McWeeny, R.; Dierksen, G. J. Chem. Phys. 1968, 49, 4852.
(26) (a) Becke, A. D. Phys. Rev. A 1988, 38, 3098. (b) Lee, C.; Yang, W.;
Parr, R. G. Phys. Rev. B 1988, 37, 785.
˚
error (0.002 A).
J. Org. Chem. Vol. 74, No. 21, 2009 8237

Krow et al.
JOCArticle
stable than fluoroiminium ion 40c. See Supporting Infor-
(entry 6). AgF/CH NO gave a mixture of difluoride 18 and
3
aldehyde 19 (entry 8). In two trials with NaN /DMF similar
3
2
2
7
mation for details on aziridinium ions 41a,b.
Considering the large energy preference calculated for the
gas phase iminium ions 40 versus the aziridinium ions 41, it is
perhaps surprising that the 5-anti-bromo-2-azabicyclo-
[2.1.1]hexanes 9-11, related to 38a-c, can undergo nucleo-
philic substitutions to afford unrearranged 5(6)-anti
to entry 3, but using less pure noncrystalline dibromide 9, a
small amount (<6%) of aldehyde 19 was obtained with air
as the only recognized oxidant. Aldehyde 19 also formed
during reactions of BAST with diol 16b (Table 1, entry 7).
For proposed mechanisms to this oxidized ring-cleaved
aldehyde 19, see Supporting Information.
products related to 42. A 1,2-alkyl shift of C from C to
1
6
C on the anti face of a cationic species 39 leads to iminium
5
ion 40. Unrearranged products 42 that have retained stere-
ochemistry are consistent with an intermediate ion that
under suitable conditions is resistant to rearrangement. Such
an ion in solution might be an aziridinium ion such as 41,
associated with its counterion.
Conclusion
The novel N-benzyl-5-anti,6-anti-dibromo-2-azabicyclo-
2.1.1]hexane nitrogen mustard 9, the bromide 10, and bromo-
[
fluoride 11 react with nucleophiles to give products with
retained stereochemistry. We have observed single bromide
displacement reactions, and somewhat slower displacements
of two bromides by appropriate oxygen (acetate), nitrogen
(azide, imidazole), thioether (phenylthio), and halide (fluoride,
iodide) nucleophiles. The present synthetic route describes
the first reported examples of 5-anti,6-anti-diols, -difluorides,
-diazides, -dithioethers, -fluoroamines, and -fluorothioethers,
as well as the first 5-anti-imidazoles. We presently envision use
of the diols, fluoroalcohols, and difluorides as key intermedi-
ates for the preparation of methanoproline derivatives, desired
in order to study substituent effects on amide conformations.
Solvent effects are consistent with the need to stabilize a
transition state leading to charged intermediates, such as
4
than DMF for the displacement reactions of all substrates
1a-c. The more polar DMSO was a more effective solvent
2
0,28
9
-11.
displacements.
CsOAc and NaOAc are illustrative. This substrate remained
4% unreacted (Table 4, entry 3) with NaOAc in DMSO
A “cesium ion effect” was also noted for acetate
2
8-30
Reactions of fluorobromide 11 with
6
solvent at 70 ꢀC after 5 days, but with CsOAc and the same
temperature/solvent conditions fluorobromide 11 reacted
completely (Table 3, entry 4). These reactions were run under
heterogeneous conditions, and thus the salt solutions were
concentrated. The greater solubility of CsOAc than NaOAc
in DMSO and DMF, as well as lesser ion pairing of cesium
salts, increases the ionic strength of the CsOAc reaction
solutions and facilitates the formation of charged ions in
Experimental Section
N-Benzyl-5-anti,6-anti-dibromo-2-azabicyclo[2.1.1]hexane (9).
To a solution of dibromide 13 (1000 mg, 2.67 mmol) in
methanol (75 mL) was added Pd(OH) (150 mg). The solution
2
7b
3
0
the polar solvents.
was degassed and stirred under a H -filled balloon for 1 h at rt.
2
Silver ions facilitated bromide displacements. The out-
comes of the silver salt reactions we investigated were
dependent upon counterion and solvent. Illustrative are the
conversions of monobromide 10 in Table 2. AgOAc/DMF
gave acetate 20a (entry 1). However, with AgF/DMF the
reaction took a different course, and an oxidative rearrange-
ment occurred to give pyrrole aldehyde 19 (entry 2). The
sodium salt NaF/DMF was unreactive with bromide 10 over
The reaction mixture was filtered through Celite, the filtrate was
evaporated, and the residue was chromatographed on silica gel
(
9:1 EtOH/MeOH) to give 513mg (80%) of dibromoamine13-int
1
at R
4
1
f
=0.58 (2:1 EtOH/MeOH); H NMR (400 MHz, CDCl
.11 (s, 2H, H and H ), 3.87 (d, J=6.0 Hz, 1H, H ), 3.35 (br s,
H, NH), 3.17 (s, 2H, 2H ), 3.10 (d, J=6.0 Hz, 1H, H );
3
) δ
5
6
1
13
C
3
4
NMR (100 MHz, CDCl3, rt) δ 66.2, 52.3, 51.2, 47.1; HRMS m/z
79/79, 79/81, 81/81
2
39.9014, 241.9001, 243.8983, calcd for C
5 8
H N
Br
2
(
(0.50 g, 2.08 mol) in acetonitrile (20 mL) were added Et N (1.69 g,
M þ H) 239.9023, 241.9003, 243.8983. To a solution of amine
12 h (entry 3), but the silver salt AgF/CH NO provided
3 2
fluoride 26 (entry 10).
3
16.60 mol) and then BnBr (1.42 g, 8.30 mol) dropwise at rt. The
reaction mixture was stirred at rt for 36 h. Solvent was removed in
vacuo, ether (75 mL) was added, the mixture was stirred for
Reactions of the alcohols 16b (25 ꢀC) and 24b (40 ꢀC) with
BAST/CH Cl to give fluorides 18 and 26 were markedly
2
2
1
ether (25 mL). Solvent again was removed in vacuo to afford
0 min at rt and then filtered, and the residue was washed with
easier than conversion of bromides 9 (50 ꢀC) or 10 (70 ꢀC) to
the fluorides, even with AgF/CH NO (Table 1, entries 7, 8
3
2
crude dibromide 9. This was chromatographed on silica gel
(
and Table 2, entries 10, 11). The hydroxyl groups are
activated for displacement by BAST after formation of O-
sulfur bonds; fluorination reactions occurred in CH Cl in a
hexanes/ether 4:1) to afford 590 mg (86%) of an off-white solid
1
dibromide 9 at R
NMR (400 MHz, CDCl
H and H ), 3.85 (s, 2H, CH Ph), 3.61 (d, J=6.6 Hz, 1H, H ), 3.12
f
=0.75 (1:1 hexanes/ether); mp 68-70 ꢀC; H
2
2
3
) δ 7.36-7.27 (m, 5H, Ph), 4.32 (s, 2H,
few hours.
5
6
2
1
1
3
The oxidative ring-opening reaction to form the aromatic
aldehyde 19 occurred under a variety of conditions. Reac-
tions of dibromide 9 in Table 1 are informative. AgF/DMF
afforded the aldehyde 19 (entry 1), but so did NaF/DMSO
(
dd, J=6.6, 0.9 Hz, 1H, H ), 2.92 (s, 2H, 2H ); C NMR (100
4 3
MHz, CDCl ) δ 137.8, 128.5, 127.4, 70.1, 58.6, 55.1, 52.4, 51.1;
3
HRMS m/z 329.9482, 331.9472, 333.9453, calcd for
7
9/79,79/81,81/81
C
3
H N
12 14
Br
33.9453. Hexanes (0.3 mL) were added to a vial with a syringe
that contained about 5 mg of dibromide 9 dissolved in ether
0.2 mL). The vial was wrapped with aluminum foil, small holes
were made with a syringe, and the solution was allowed to sit for
(M
þ
H) 329.9493, 331.9473,
2
(
27) Independently, the aziridinium ions 41a,b were drawn and their
(
geometries were optimized using both methods 1 and 2. The aziridinium
ions 41a,b were calculated to be 42-46 kcal/mol less stable than the
corresponding iminium ions. See Supporting Information for details.
3
d to give crystals suitable for X-ray crystallography.
N-(Benzyloxycarbonyl)-5-anti-bromo-2-azabicyclo[2.1.1]hexane
(
28) Dijkstra, G.; Kruizinga, W. H.; Kellog, R. M. J. Org. Chem. 1987, 52,
230–4234.
29) (a) Salvatore, R. N.; Nagle, A. S.; Schmidt, S. E.; Jung, K. W. Org.
4
(
(
(
14). To a solution of dibromide 13 (693 mg, 1.8 mmol) in toluene
50 mL) were added (TMS) SiH (596 μL, 1.9 mmol) and AIBN
40 mg). The resulting solution was allowed to stir at 70 ꢀC for 3 h.
(
3
Lett. 1999, 1, 1893. (b) Salvatore, R. N.; Nagle, A. S.; Jung, K. W. J. Org.
Chem. 2002, 67, 674.
(30) Shukla, R.; Kida, T.; Smith, B. D. Org. Lett. 2000, 2, 3099.
The solvent was concentrated in vacuo, and flash chromatography
8
238 J. Org. Chem. Vol. 74, No. 21, 2009

Krow et al.
JOCArticle
1
9
gave 407 mg (74%) of the monobromide 14 at R = 0.39 (2:1
f
Hz); F NMR (282 MHz, CDCl ) δ -208.68 (d, J=60.6 Hz);
HRMS m/z 270.0275, calcd for C12H13BrFN (M) 270.0288.
3
1
hexanes/ether); H NMR (400 MHz, CDCl
3
) δ 7.11 (m, 5H), 4.91
), 3.58 (d, J=8.4 Hz, H ), 3.27 (d, J
9.0 Hz, H ), 3.23 (d, J=9.0 Hz, H ), 2.79 (dm, J=8.1 Hz, H6anti),
(
=
s, 2H), 4.19 (br d, J=6.3 Hz, H
5
1
N-Benzyl-5-anti,6-anti-diacetoxy-2-azabicyclo[2.1.1]hexane
(16a) and N-Benzyl-5-anti-acetoxy-6-antibromo-2-azabicyclo-
[2.1.1]hexane (17). General Method A (DMF). To a solution of
dibromide 9 (200 mg, 0.604 mmol) in DMF (20 mL) under
argon was added cesium acetate (696 mg, 3.63 mmol). After
stirring at 60 ꢀC for 5 days, the reaction mixture was allowed to
reach rt. Brine (10 mL) was added, and the solvent was
extracted with ether (3 ꢀ 20 mL). The combined ether extracts
were washed with water (20 mL) and dried over Na SO . The
3
3
13
2
.67 (br, 1H, H
MHz, CDCl ) δ 155.5, 136.9, 128.9, 128.5, 128.4, 68.6, 65.2, 55.2,
9.4, 46.3, 39.3 and 25.5; HRMS m/z found 296.0284, calcd for
4
), 1.40 (dd, J=8.1, 6.3 Hz, H6syn); C NMR (100
3
4
C H NO Br (M þ H) 296.0281, m/z 318.0105 calcd for
13
14
2
C
13
H
13NO
2
BrNa (M þ Na) 318.0105.
N-Benzyl-5-anti-bromo-2-azabicyclo[2.1.1]hexane (10). To a
solution of the monobromide 14 (708 mg, 2.4 mmol) in MeOH
40 mL) was added Pd(OH) (71 mg), and the resulting solution
2
4
(
dried ether was evaporated, and the residue was chromato-
graphed on silica gel (hexanes/ether 2:1) to give 70 mg (40%) of
2
was degassed and allowed to stir for 1 h at rt under hydrogen.
After 1 h the catalyst was filtered via Celite, and the solvent was
removed in vacuo to give 500 mg of the crude amine. Without
further purification the amine was dissolved in acetonitrile
diacetate 16a as an orange colored oil at R
ether), 78 mg (42%) of bromoacetate 17 as an orange colored
oil at R =0.53 (1:1 hexanes/ether), and 19 mg (10%) of starting
material. For diacetate 16a: H NMR (400 MHz, CDCl
7.43-7.23 (m, 5H, Ph), 4.99 (s, 2H, H and H ), 3.91 (s, 2H,
f
=0.27 (1:1 hexanes/
f
1
(
20 mL), and to the resulting solution were added Et
405 mg, 4.0 mmol) and BnBr (328 mg, 1.9 mmol). The resultant
3
N
3
) δ
(
solution was stirred at rt for 3 days. Solvent was removed in
5
6
CH Ph), 3.56 (d, J=6.9 Hz, 1H, H ), 3.04 (d, J=6.9 Hz, 1H,
2
1
1
3
vacuo to give an oil that on flash chromatography gave 351 mg
(
H
4
), 3.03 (s, 2H, 2H
3
), 2.10 (s, 6H, 2COCH
3
); C NMR (100
and
C ), 65.5, 58.6, 52.2, 47.7, 21.0; HRMS m/z 290.1399, calcd for
1
= 0.40 (1:1 hexane/ether); H
58%) of the bromide 10 at R
f
3 5
MHz, CDCl ) δ170.8, 138.2, 128.7, 128.4, 127.3, 81.7 (C
NMR (400 MHz, CDCl ) δ 7.39-7.24 (m, 5H), 4.11 (d, J =
3
6
1
8
.4 Hz, 1H, H ), 3.81 (s, 2H), 3.46 (dd, J=6.9, 1.9 Hz, H ), 2.88
C H NO (M þ H) 290.1392. For bromoacetate 17:
H
5
1
16 20
4
1
3
(
m, 4H, 2H
3
, H
4
, H6anti), 1.76 (t, J=8.1 Hz, H6syn); C NMR
) δ 139.0, 128.5, 128.3, 127.0, 68.8, 59.0, 55.3,
4.6, 48.0, 35.8; HRMS m/z found 252.0383, calcd for
15NBr (M þ H) 252.0383.
N-(Benzyloxycarbonyl)-5-anti-bromo-6-anti-fluoro-2-azabicyclo-
2.1.1]hexane (15). To a solution of 2-azabicyclo[2.2.0]hex-5-ene
NMR (400 MHz, CDCl ) δ 7.41-7.27 (m, 5H, Ph), 4.91 (d,
J=7.0 Hz, 1H), 4.34 (d, J=7.1 Hz, 1H), 3.94 (d, J=13.1 Hz,
3
(
100 MHz, CDCl
3
5
C
1H), 3.86 (d, J=13.1 Hz, 1H), 3.62 (d, J=6.7 Hz, 1H, H ), 3.11
1
12
H
(d, J=6.7 Hz, 1H, H
0
4
), 3.04 (d, J=8.8 Hz, 1H, H
3
), 2.92 (br,
1
3
1H, H
137.7, 128.6, 128.5, 127.4, 82.3, 68.2, 58.4, 53.7, 50.3, 50.0,
3
), 2.13 (s, 3H); C NMR (100 MHz, CDCl ) δ170.9,
3
[
1
7b
2
(1.30 g, 0.006 mol) in MeNO (50 mL) was added NBS (2.15 g,
2
21.2; HRMS m/z 310.0410, 312.0424, calcd for C H -
14 17
7
9,81
0.012 mol) at 0 ꢀC followed by Et
3
N 3HF (2.92 g, 0.018 mol)
NO
2
Br (M þ H) 310.0443, 312.0422.
3
1
2
dropwise over a period of 10 min. The reaction was brought to rt
and stirred for 20 h. Then the reaction mixture was diluted with
CH Cl (125 mL) and washed with saturated aqueous NaHCO
N-Benzyl-5-anti,6-anti-dihydroxy-2-azabicyclo[2.1.1]hexane
(16b). To a solution of diacetate 16a (50 mg, 0.173 mmol)
in methanol (3 mL) under argon was added triethylamine
(175 mg, 1.728 mmol). The solution was stirred at rt overnight
and concentrated under reduced pressure. Purification of the
obtained residue by flash chromatography (9.5:0.5 CH Cl /
2
2
3
solution (50 mL). The organic layer was dried over anhydrous
Na SO and concentrated in vacuo, and the residue was purified by
flash chromatography (1:3 ether/hexanes) to afford 997 mg (53%)
2
4
2
2
of bromofluoride 15 as a colorless oil at R = 0.49 (1:1 ether/
f
MeOH) afforded 27 mg (76%) of diol 16b as a light orange oil
1
hexanes); H NMR (400 MHz, CDCl
1
/MeOH 9:1); H NMR (400 MHz, CDCl
3
) δ 7.41-7.29 (m, 5H),
at R
f
=0.54 (CH
2
Cl
2
3
)
5
5
.18 (d, J=12.3 Hz, 1H), 5.14 (d, J=12.3 Hz, 1H), 4.99 (dd, J=
9.1, 7.3 Hz, 1H, H ), 4.55 (br d, J=7.2 Hz, 1H, H ), 4.11 (dd,
δ 7.40-7.28 (m, 5H), 4.59 (s, 2H, H
(br, 2H, 2OH), 3.21 (d, J=7.0 Hz, 1H, H ), 2.97 (s, 2H, 2H ),
5
and H ), 3.89 (s, 2H), 3.57
6
5
6
1
3
1
); C NMR (100 MHz, CDCl
3
J=7.3, 3.1 Hz, 1H, H
1
), 3.61 (ddd, J=9.1, 3.2, 1.2 Hz, 1H, H
.51 (dt, J= 9.1, 1.3 Hz, 1H, H ), 3.13 (brdd, J= 7.3, 3.6 Hz,
); C NMR (100 MHz, CDCl ) δ 154.9, 136.0, 128.5,
28.3, 128.0, 99.7 (JC,F=226.8 Hz), 67.4, 64.6, 49.8, 49.1 (JC,F
3
),
2.64 (d, J=6.9 Hz, 1H, H
137.7, 128.8, 128.5 and 127.4, 81.9 (C
4
3
) δ
and C ), 67.9, 58.9, 52.7,
3
1
1
1
3
0
5
6
1
3
H, H
4
3
50.4; HRMS m/z 206.1173, calcd for
(M þ H) 206.1181.
12 2
C H16NO
=
19
7.5 Hz), 48.1; F NMR (282 MHz, CDCl
3
) δ -204.75 (d, J=58.9
N-Benzyl-5-anti,6-anti-difluoro-2-azabicyclo[2.1.1]hexane (18)
and N-Benzyl-3-formylpyrrole (19) (from diol 16b). To a solution
of diol 16b (25 mg, 0.122 mmol) in CH Cl (0.7 mL) under argon
Hz), -205.83 (d, J = 58.9 Hz); HRMS m/z found 336.0014,
79 and 81
38.0005, calcd for C H NO FBr
3
Na (M þ Na)
13
13
2
2
2
336.0011, 337.9991.
was added BAST (81 mg, 0.365 mmol) dropwise at -78 ꢀC. The
resulting mixture was brought to rt and stirred overnight. The
N-Benzyl-5-anti-bromo-6-anti-fluoro-2-azabicyclo[2.1.1]hexane
11). To a solution of fluorobromide 15 (990 mg, 3.2 mmol) in
(
methanol (25 mL) was added Pd(OH) (99 mg). The solution was
degassed in vacuo for 5 min and stirred at rt under a H balloon
2 2
solution was diluted with CH Cl (1.3 mL) and washed with brine
(0.5 mL) and water (0.5 mL), and then the CH Cl layer was dried
2
2
2
2
2 4
over Na SO . The organic layer was concentrated under reduced
for 1 h. The reaction mixture was then filtered through Celite, the
solvent was removed in vacuo, the crude amine was dissolved in
CH CN (17 mL), and then Et N (1.3 g, 4 mmol) followed by
BnBr (807 mg, 1.5 mmol) were added dropwise. The solution was
stirred at rt for 3 days followed by removal of solvent in vacuo to
give the residue, which was chromatographed to give 494 mg
pressure, and purification of obtained residue by preparative
TLC (1:1 hexanes/ether) gave 6 mg (24%) of difluoro compound
18 at R =0.37 (1:1 hexanes/ether) and 9 mg (40%) aldehyde 19 at
3
3
f
1
R
CDCl
f
= 0.13 (1:1 hexanes/ether). For 18: H NMR (400 MHz,
0
0
3
) δ 7.35-7.25 (m, 5H), 5.34 (m, AA XX pattern, 2H, H
5
and H ), 3.82 (s, 2H), 3.45 (dt, J=7.2, 1.9 Hz, 1H, H ), 2.99 (m,
1H, H ), 2.92 (s, 2H, 2H ); C NMR (100 MHz, CDCl ) δ 138.1,
4 3 3
6
1
13
(
58%) of bromoamine 11 as a light orange oil at R =0.79 (1:5
f
1
0
0
ether/hexanes); H NMR (400 MHz, CDCl
5
1
3
) δ 7.40-7.25 (m,
), 4.39 (dd, J=7.4, 3.2 Hz,
H, H ), 3.88 (d, J=13.2, 1H), 3.77 (d, J=13.2, 1H), 3.55 (dd,
128.4 (2C), 127.3, 100.6, and 98.3 (m, AA XX pattern, 2C, C
and C ), 65.5 (t, J=18.2 Hz, C ), 58.7, 50.5 (t, J=7.3 Hz), 49.2 (t,
J=18.1 Hz, C4); F NMR (282 MHz, CDCl ) δ -217.3 (m).
5
H), 5.17 (dd, J=60.6, 7.3 Hz, 1H, H
5
6
1
1
9
6
3
J=6.8, 1.8 Hz, 1H, H
1
), 3.07 (ddt, J=6.8, 4.4, and 1.2 Hz, 1H,
), 2.74 (ddd, J=9.0, 4.0,
); C NMR (100 MHz, CDCl ) δ 137.9, 128.4 (2C
overlap), 127.3, 100.1 (JC,F=222.3 Hz), 68.4 (JC,F=18.7 Hz, C1),
8.5, 52.9 (JC,F=5.0 Hz), 51.4 (JC,F=17.1 Hz, C ), 49.4 (JC,F=3.0
HRMS m/z 210.1089, calcd for C12
H14NF
2
(M þ H) 210.1094.
H
4
), 3.03 (dt, J=9.0 and 1.2 Hz, 1H, H
3
N-Benzyl-5-anti,6-anti-diazido-2-azabicyclo[2.1.1]hexane (20)
and N-Benzyl-6-anti-azido-5-anti-bromo-2-azabicyclo[2.1.1]hexane
(21) (DMF). According to general method A, sodium azide
(15 mg, 0.24 mmol) was added to a solution of crystalline
13
1
.2 Hz, 1H, H
3
0
3
5
4
J. Org. Chem. Vol. 74, No. 21, 2009 8239

Krow et al.
JOCArticle
dibromide 9 (15 mg, 0.045 mmol) in DMF (2.5 mL) under an air
atmosphere. The mixture was allowed to stir at 60 ꢀC for 8 d.
Workup and chromatography of the residue using silica gel (5:1
hexane/ether) gave 9.3 mg of a mixture of dibromide 9 (2.6 mg),
8.1 Hz, H6anti), 2.54 (dd, J = 6.8, 3.0 Hz, 1H, H ), 2.48 (d,
4
1
3
J = 8.8 Hz, H
(100 MHz, CDCl
46.1, 32.3; HRMS m/z 190.1212, calcd for C H NO (M þ H)
3
), 1.74 (dd, J = 8.1, 7.2 Hz, H6syn); C NMR
3
) δ 128.7, 128.3, 126.9, 80.6, 67.3, 59.1, 55.0,
1
2
15
2
.8 mg (34%) of diazide 20 at R
f
=0.5 (1:1 hexane/ether), and
=0.6. In two trials with
noncrystalline dibromide 9 a small amount (<6%) of aldehyde 19
190.1227.
4.0 mg (49%) of bromoazide 21 at R
f
N-(tert-Butoxycarbonyl)-5-anti-hydroxy-2-azabicyclo[2.1.1]hexane
(25). To a solution of alcohol 24b (25 mg, 0.13 mmol) in MeOH
(8 mL) was added Pd(OH)2 (5 mg) and (BOC) O (54 mg,
1
was observed at R =0.35. For diazide 20: H NMR (CDCl , 400
f
3
2
Hz) δ 7.25 (m, 5H), 4.14 (s, 2H), 3.75 (s, 2H), 3.31(d, J=7.0 Hz,
0.25 mmol). The solution was stirred under 1 atm of hydrogen
for 7 h at rt. Afterward, the solution was diluted with 10 mL of
MeOH and filtered through Celite. Evaporation of the solvent
13
1 3 4
1H, H ), 2.85 (s, 2H, 2H ), 2.81(d, J=7.0 Hz, 1H, H ); C NMR
(
CDCl , 100 Hz) δ 138.4, 128.9, 128.9, 127.8, 68.4, 67.3, 59.0, 53.9,
3
4
2
8.2; HRMS m/z calcd for C H N (M þ H) 256.1259, found
followed by column chromatography gave 24 mg (92%) of
1
2
14
7
1
56.1263. For bromoazide 22: H NMR (CDCl
1
3
, 400 Hz) δ=7.25
the pure alcohol 25 at R
(300 MHz, CDCl ) δ 4.17 (m, 2H, H
2H ), 2.93 (dm, J=7.5 Hz, 1H, H ), 2.70 (m, 1H, H
f
=0.31 (2:1 hexane/ether); H NMR
(m, 5H), 4.22 (d, J=7.0 Hz, 1H), 4.18 (d, J=7.0Hz, 1H), 3.77 (two
d, J=13.2 Hz, 2H, CH Ph), 3.41 (d, J=6.6 Hz, 1H, H ), 2.93 (m,
3
1
and H
5
), 3.32 (s, 2H,
), 1.81
2
1
3
4
6anti
13
13
2H, H
3
þH
4
), 2.72 (d, J=9.1 Hz, 1H, H
3
); C NMR (CDCl , 100
3
(br, OH), 1.61 (t, J=7.5 Hz, 1H, H6syn), 1.45 (s, 9H); C NMR
(100 MHz, CDCl ) δ 155.7, 81.4, 79.5, 63.4, 48.3, 44.1, 36.9,
Hz) δ 138.3, 128.9, 128.9, 127.8, 69.8, 68.9, 59.0, 54.8, 50.5 (2C);
HRMS m/z 294.0483, calcd for C12
3
7
9
H
14
N
4
Br (MBr þ H)
28.5; HRMS m/z found 222.1104, calcd for C10
3
H17NO Na
8
1
2
94.0481 and 296.0465, calcd for C H N Br (MBr þ H)
(M þ Na) 222.1104.
1
2
14
4
2
96.0461.
N-Benzyl-5-anti-6-anti-di(phenylthio)-2-azabicyclo[2.1.1]hexane
22) and N-Benzyl-5-anti-bromo-6-anti-(phenylthio)-2-azabicyclo-
2.1.1]hexane (23). General Method B (DMSO). To a solution
N-Benzyl-5-anti-fluoro-2-azabicyclo[2.1.1]hexane (26) (from
bromide 10 using AgF). To a solution of bromide 10 (33 mg,
0.13 mmol) in CH NO (8 mL) at rt under argon was added AgF
(
[
3
2
(83 mg, 0.65 mmol), and the reaction mixture was heated at
50 ꢀC for 12 h. The AgF was filtered via Celite, and the solvent
was removed in vacuo to give 20 mg (80%) of pure fluoride 26 at
of dibromide 9 (50 mg, 0.15 mmol) in dry DMSO (1 mL) was
added NaSPh (120 mg, 0.906 mmol) under argon, and the
reaction mixture was maintained at 60 ꢀC for 5 h. The usual
workupandchromatography(prep TLC, 1:2 ether/hexanes) gave
di(phenylthio) ether 22 (22 mg, 37%) at R = 0.53 (1:2 ether/
hexanes) and bromo(phenylthio) ether 23 (16 mg, 29%) at R =
1
R = 0.20 (1:2 hexane/ethyl acetate); H NMR (300 MHz,
f
CDCl
J=13.8 Hz, 1H, CH
J=6.4 Hz, H ), 2.88 (b, J=8.8 Hz, H
2H, H and H6anti), 1.90 (ddd, J=8.0, 7.2, 2.4 Hz, H6syn);
3
) δ 7.36 (m, 5H), 4.90 (dd, J=64, 7.2 Hz, H
), 3.65 (d, J=13.8 Hz, 1H, CH ), 3.35 (brd,
), 2.72 (br, H ), 2.51 (m,
5
), 3.74 (d,
f
2
2
f
3
3
4
1
3
0
starting dibromide 9 (2 mg, 4%) at R
.59 (1:2 ether/hexanes) as light orange-colored oils and the
0.73 (1:2 ether/hexanes)
C
3
f
NMR (75 MHz, CDCl
208 Hz), 65.8 and 65.6, 58.9, 53.5, 45.3, 32.1; F NMR (282
MHz, CDCl ) δ -220.1 (d, J = 64.7 Hz); HRMS m/z found
3
) δ 138.6, 128.7, 128.4, 127.2, 98.8 (d, J=
1
19
as an off-white solid. For di(phenylthio) ether 22: H NMR (400
MHz, CDCl and H ),
.80 (s, 2H, CH Ph), 3.71 (d, J=6.6 Hz, 1H, H ), 3.16 (d, J=6.6
) δ 7.44-7.23 (m, 15H), 3.94 (s, 2H, H
5
5
0
3
3
3
192.1191, calcd for C H NF (M þ H) 192.1188.
2
1
12 14
1
3
Hz, 1H, H
4
), 306 (s, 2H, H ); C NMR (100 MHz, CDCl
3
3
) δ
N-Benzyl-5-anti-azido-2-azabicyclo[2.1.1]hexane (27). Method
A (DMF). To a solution of bromide 10 (65 mg, 0.24 mmol) in
DMF (10 mL) under argon was added sodium azide (84 mg, 1.3
mmol). The resulting solution was heated for 12 h at 70 ꢀC. The
1
5
38.5 (br, 2C), 129.2, 129.0, 128.5, 128.4, 127.2, 126.1, 71.3, 58.9,
6.8, 56.6, 51.6; HRMS m/z 390.1361 calcd for C H NS (M þ
2
4
24
2
1
H) 390.1345. For bromo(phenylthio) ether 23: H NMR (400
MHz, CDCl ) δ 7.37-7.18 (m, 10H), 4.27 (d, J=7.3 Hz, 1H, H ),
.88 (d, J = 13.3 Hz, 1H, CH Ph), 3.83 (d, J = 13.3 Hz, 1H,
3
6
usualworkupand flashchromatographygave 28mg (51%) of the
1
=0.39 (1:1 hexane/ether); H NMR (300 MHz,
3
2
azide 27 at R
f
CH Ph), 3.74 (d, J=7.3 Hz, 1H, H ), 3.64 (d, J=6.5 Hz, 1H, H ),
2
CDCl ) δ 7.38 (m, 5H), 3.86 (br, J=7.5 Hz, H ), 3.72 (d, J=13.2
5
1
3
5
3
=
.13 (d, J=6.5 Hz, 1H, H
4
), 2.97 (d, J=8.9 Hz, 1H, H ), 2.94 (d, J
3
Hz, 1H), 3.65 (d, J=13.2 Hz, 1H), 3.32 (dd, J=6.3, 2.0 Hz, H
2.86 (brd, J=9.3 Hz, H ), 2.67 (m, H ), 2.61 (d, J=9.3 Hz, H
2.38 (brd, J=7.8 Hz, H6anti), 1.69 (dd, J=7.8, 7.5 Hz, H6syn);
1
),
),
C
1
3
); C NMR (100 MHz, CDCl
8.9 Hz, 1H, H
3
3
) δ 139.1, 138.0,
3
4
3
3
1
1
5
3
29.3, 129.0, 128.5, 128.5, 127.4, 126.2, 71.2, 58.8, 58.3, 55.9, 52.7,
2.0; HRMS m/z 360.0433 calcd for C H BrNS (M þ H)
NMR (100 MHz, CDCl ) δ 129.0, 128.8, 127.5, 69.5, 67.0, 59.2,
1
8
19
3
60.0416.
54.9, 45.2 and 33.8; HRMS m/z found 215.1291, calcd for
(M þ H) 215.1282; m/z found 256.1551, calcd for
N-Benzyl-5-anti-acetoxy-2-azabicyclo[2.1.1]hexane (24a) (DMF).
Following general method A, to a solution of bromide 10 (14 mg,
.06 mmol) in DMF (8 mL) under argon was added (72 mg,
.5 mmol) of AgOAc. The resulting solution was heated for 12 h
at 70 ꢀC. Workup and chromatography gave 7 mg (54%) of acetate
C H N
12 15 4
C H N (M þ CH CN þ H) 256.1556.
14
18
5 3
0
0
N-Benzyl-5-anti-(tert-butoxycarbonylamino)-2-azabicyclo-
[2.1.1]hexane (28). To a solution of azide 27 (29 mg, 0.13 mmol)
3
in toluene (8 mL) were added PPh (71 mg, 0.27 mmol) and
water (1 mL), and the resultant solution was heated at 60 ꢀC for
4 h. After cooling, the two layers were separated, and the water
1
24a at R =0.28 (1:1 hexane/ethyl acetate); H NMR (300 MHz,
f
CDCl
H, CH
), 2.88 (d, J=8.7 Hz, H
J=7.8 Hz, H6anti), 2.03 (s, 3H), 1.73 (dd, J=7.8, 7.5 Hz, H6syn);
NMR (100 MHz, CDCl ) δ 171.1, 130.0, 128.8, 128.4, 127.2, 81.4,
5.5, 58.5, 54.0, 44.4, 32.3, 21.0; HRMS m/z found 232.1315, calcd
3
) δ 7.24 (m, 5H), 4.73 (d, J=7.5 Hz, H
), 3.74 (d, J=13.1 Hz, 1H, CH ), 3.39 (dd, J=6.6, 1.5 Hz,
), 2.74 (m, 2H, H and H ), 2.42 (d,
5
), 3.82 (d, J=13.1 Hz,
1
H
1
2
2
layer was extracted with CH
were combined and dried over Na
in vacuo, and the amine was dissolved in MeOH to which were
added Et N (18 μL, 0.26 mmol) and (BOC) O (28 mg, 0.13
2
Cl
2
(3 ꢀ 5 mL). All organic layers
3
4
3
2
SO . Solvent was removed
4
13
C
3
3
2
6
mmol). Removal of the solvent followed by flash chromatog-
raphy gave 34 mg (87%) of the BOC protected amine 28 at R =
for C H NO (M þ H) 232.1315.
14
18
2
f
1
N-Benzyl-5-anti-hydroxy-2-azabicyclo[2.1.1]hexane (24b). To
a solution of acetate 24a (3 mg, 0.002 mmol) in methanol (3 mL)
was added K CO (138 mg, 0.01 mmol), and the solution was
0.37 (1:3 hexane/ethyl acetate); H NMR (300 MHz, CDCl ) δ
3
7.44 (m, 5H), 4.92 (br, 1H, NH), 3.82 (s, 2H), 3.76 (br, H
(br, H ), 2.86 (d, J=8.1 Hz, H ), 2.72 (br, 2H, H and H
(brd, J=7.8 Hz, H6anti), 1.74 (dd, J=7.8, 8.1 Hz, H6syn), 1.35 (s,
5
), 3.40
), 2.32
2
3
1
3
3
4
stirred at rt for 1 h. After 1 h the base was filtered, and the solvent
was removed in vacuo to give 2.1 mg (84%) of the alcohol 24b at
1
3
9H); C NMR (100 MHz, CDCl
128.8, 127.5, 119.5, 79.9, 66.5, 59.0, 55.2, 44.7, 34.3, 34.2, 28.8;
HRMS m/z found 289.1917, calcd for C17
(M þ H)
289.1911; m/z found 311.1749, calcd for C H N O Na
3
) δ 156.4, 139.3, 128.9 and
1
= 0.20 (1:2 hexane/ethyl acetate); H NMR (300 MHz,
R
CDCl
f
3
) δ 7.36 (m, 5H), 4.18 (brd, J = 7.2 Hz, H
5
), 3.78 (d,
25 2 2
H N O
J=12.9 Hz, 1H, CH ), 3.69 (d, J=12.9 Hz, 1H, CH ), 3.19 (d, J=
6
2
2
17 24
2
2
.8, 1.8 Hz, H
1
), 2.96 (d, J = 8.8 Hz, H
3
), 2.64 (brd, J =
(M þ Na) 311.1730.
8
240 J. Org. Chem. Vol. 74, No. 21, 2009

Krow et al.
JOCArticle
1
N-Benzyl-5-anti-imidazol-1-yl-2-azabicyclo[2.1.1]hexane (29).
Butyllithium (90 μL, 2.5 M solution in hexanes, 0.226 mmol)
was added dropwise to imidazole (15 mg, 0.226 mmol) in
anhydrous DMF (0.5 mL) under argon, and the mixture was
stirred at 20 ꢀC for 0.25 h. A solution of bromide 10 (19 mg, 0.075
mmol) in anhydrous DMF (0.5 mL) was added, and after stirring
2.79-2.62 (m, 2H, 2H ), 2.01 (s, 3H); H NMR (400 MHz, C D )
3
6
6
δ7.44-7.22(m, 5H), 5.21-4.96 (m, ABX pattern, 2H, H
5
and H
6
),
3.61 (d, J=13.2, Hz, 1H), 3.55 (d, J=13.2, Hz, 1H), 3.51 (dd, J=
7.1, 2.1 Hz, 1H, H ), 2.78 (m, 1H, H ), 2.57 (br d, J=9.0 Hz, 1H,
1
4
1
3
H
3
), 2.50 (ddd, J=9.0, 3.6, 1.2 Hz, 1H, H
(100 MHz, CDCl ) δ 171.2, 138.2, 128.5, 128.4 and 127.2, 99.5
(JC,F=219.0 Hz, C ), 81.3 (JC,F=3.6 Hz), 65.5 (JC,F=18.4 Hz, C ),
58.7, 51.4 (JC,F=6.7 Hz), 48.4 (JC,F=17.7 Hz, C ), 21.0; F NMR
3
), 1.92 (s, 3H); C NMR
3
at 70 ꢀC for 8 days, workup, and chromatography (CH
MeOH/ NH OH 90: 10: 1) the imidazolyl compound 29 was
2 2
Cl /
5
1
1
9
4
4
isolated as a light orange-colored oil (10 mg, 55%) at R
f
=0.60
OH, 90:10:1); HNMR (400 MHz, CDCl
δ 7.54 (s, 1H), 7.43-7.25 (m, 5H), 7.09 (s, 1H), 6.94 (s, 1H), 4.30
d, J=7.3 Hz, 1H, H ), 3.91 (d, J=13.2 Hz, 1H, Bn), 3.83 (d,
(282 MHz, CDCl
250.1224, calcd for C14
N-Benzyl-5-anti-fluoro-6-anti-hydroxy-2-azabicyclo[2.1.1]hexane
(32b). To a solution of fluoroacetate 32a (575 mg, 2.306 mmol) in
3
) δ -214.63 (d, J=60.9 Hz); HRMS m/z
17FNO
1
(
CH
2
Cl
2
/MeOH/NH
4
3
)
H
2
(M þ H) 250.1238.
(
5
J=13.2Hz, 1H, Bn), 3.70 (dbr, J=6.8 Hz, 1H, H
H, H ), 2.79 (d, J=8.7 Hz, 1H, H6anti), 2.13 (m, 1H, H
two d, J=8.5, 8.5 Hz, 1H, H6syn); CNMR (100 MHz, CDCl ) δ
1
), 3.14-3.07 (m,
3
methanol (35 mL) under argon was added Et N (3212 μL, 23.066
mmol). The solution was stirred at rt for 20 h and concentrated
under reduced pressure. Purification of the obtained residue by
2
(
3
4
), 1.88
1
3
3
1
38.7, 136.8, 129.4, 128.6, 128.5, 127.3, 119.0, 66.1, 64.4, 58.9,
4.6, 44.1, 33.4; HRMS m/z 240.1495, calcd for C15H
18
flash chromatography (0.5:9.5 MeOH/CH
(96%) of fluoroalcohol 32b at R =0.62 (1:9 MeOH/CH
NMR (400 MHz, CDCl ) δ 7.40-7.19 (m, 5H), 5.41 (dd, J=61.8,
8.0 Hz, 1H, H ), 4.56 (d, J=8.0 Hz, 1H, H ), 3.83 (s, 2H), 3.33 (dd,
2 2
Cl ) afforded 459 mg
1
5
H) 240.1495.
N
3
(M þ
f
2 2
Cl ); H
3
N-Benzyl-5-anti-phenylthio-2-azabicyclo[2.1.1]hexane (30).
Following method B, to a solution of monobromide 10
5
6
J=7.2, 2.1 Hz, 1H, H
(brdd, J=7.2, 5.2, Hz, 1H, H
1
and br, 1H, OH), 2.93 (s, 2H, 2H ), 2.82
3
13
(
(
22 mg, 0.087 mmol) in dry DMSO (0.6 mL) was added NaSPh
35 mg, 0.262 mmol), and the reaction mixture was maintained
4
); C NMR (100 MHz, CDCl ) δ
3
137.8, 128.6, 128.5 and 127.4, 102.2 (JC,F=208.7 Hz, C ), 82.4, 66.9
(JC,F=16.3 Hz, C ), 58.8, 51.6 (JC,F=7.8 Hz), 50.2 (JC,F=16.3 Hz,
5
at 60 ꢀC for 5 h under argon. Workup and chromatography
1
19
(
(
prep TLC, 1:1 ether/hexanes) afforded phenylthio ether 30
19 mg, 77%) at R =0.42 (1:1 ether/hexanes) as a light orange
4 3
C ); F NMR (282 MHz, CDCl ) δ -213.63 (dd, J=62.4, 3.9 Hz);
f
the extra 3.9 Hz may be due to H-bonding. Calculated couplings for
the related N-methyl fluoroalcohol are 62.53 and 11.8 Hz; HRMS
1
colored oil; H NMR (400 MHz, CDCl ) δ 7.50-7.23 (m,
3
1
0H), 3.96 (d, J=13.3 Hz, 1H, CH
H, CH Ph), 3.72 (d, J=8.0 Hz, 1H, H
), 2.99 (dd, J = 8.7, 1.0 Hz, 1H, H
J=8.7, 1.0 Hz, 1H, H ), 2.88 (m, 1H, H6syn), 2.84 (m, 1H, H4),
2
Ph), 3.91 (d, J=13.3 Hz,
), 3.54 (dbr, J=6.6, 1.8
), 2.93 (dd,
m/z 208.1109, calcd for C12
H
15FNO (M þ H) 208.1132.
1
2
5
N-(tert-Butoxycarbonyl)-5-anti-fluoro-6-anti-hydroxy-2-azabi-
cyclo[2.1.1]hexane (33). To a solution of fluoroalcohol 32b
(250 mg, 1.206 mmol) in MeOH (10 mL) were added palladium
Hz, 1H, H
1
3
3
1
3
1
1
5
.81 (t, J=8.0 Hz, 1H, H6yn); C NMR (100 MHz, CDCl
38.9, 136.9, 128.9, 128.7, 128.6, 128.4, 127.1, 125.8, 67.3, 58.8,
5.8, 54.4, 45.0, 35.7; HRMS m/z 282.1321 calcd for C18
3
) δ
2
hydroxide (20 wt % Pd on carbon) (38 mg) and (Boc) O (316 mg,
1.447 mmol). The resulting solution was stirred at rt under
hydrogen for 6 h. Then the solution was filtered through Celite
and washed with MeOH (10 mL). The filtrate was evaporated to
give an oily solid, n-heptane (20 mL) was added to the residue,
and solvent was again evaporated. Then n-heptane (30 mL) was
added to the residue, and after 2 h of stirring at rt, the separated
solid was filtered and dried under reduced pressure to afford
H
20NS
(
M þ H) 282.1311.
N-Benzyl-5-anti-iodo-2-azabicyclo[2.1.1]hexane (31). A solu-
tion of NaI (190 mg, 1.269 mmol) in acetone (750 μL) was added
to bromide 10 (16 mg, 0.063 mmol) under argon. The reaction
mixture was maintained at reflux for 4 days. The solvent was
removed in vacuo, and the crude was dissolved in CH
and washed with water (2 mL). The organic layer was separated,
2
Cl
2
(4 mL)
f
237 mg (91%) of fluoroalcohol 33 as an off-white solid at R =
1
2 2
0.71 (1:9 MeOH/CH Cl ); mp 95-97 ꢀC; H NMR (400 MHz,
and the aqueous layer was washed with CH Cl (2 ꢀ 2 mL). The
CDCl ) δ 5.10 (dd, J=60.8, 7.8 Hz, 1H, H ), 4.28 (d, J=7.7 Hz,
2
2
3
5
organic extracts were combined and dried over Na
solvent was removed in vacuo, and the crude was chromato-
2
SO4. The
6 1 3
1H, H ), 4.22 (br s, 1H, H ), 3.47 (d, J=9.1 Hz, 1H, H ), 3.40 (d,
J=9.0 Hz, 1H, H ), 3.08 (br s, 1H, OH), 2.83 (br t, J=6.1 Hz, 1H,
0
3
1
), 1.43 (s, 9H); C NMR (100 MHz, CDCl
3
graphed (prep TLC, 1:1 ether/hexanes) to give iodide 31 (14 mg,
7
H
4
3
) δ 154.9, 101.9
4%) at R =0.74 (1:1 ether/hexanes) as a light orange-colored
f
(JC,F=214.2 Hz, C ), 84.1, 80.4, 63.8 (br), 48.1 (JC,F=16.3 Hz),
5
1
19
3
46.0(br), 28.3; F NMR (282 MHz, CDCl ) δ -209.3(d, J=57.6
oil; H NMR (400 MHz, CDCl
J=9.0 Hz, 1H, H ), 3.80 (two d, J=13.3, 13.3 Hz, 2H, Bn), 3.46
dd, J=6.5, 1.8 Hz, 1H, H ), 2.86-2.77 (m, 4H, 2H , H and
3
) δ 7.38-7.24 (m, 5H), 3.95 (d,
5
Hz), -210.3 (d, J=57.6 Hz) (no F-HO splitting was observed.);
HRMS m/z 240.1018, calcd for C H FNO Na (M þ Na)
(
1
3
4
10 16
3
1
3
H6 ), 1.75 (dd, J=9.0, 8.0 Hz, 1H, H ); CNMR (100 MHz,
240.1012.
anti
6syn
CDCl
3
) δ139.0, 128.5, 128.4, 127.1, 69.5, 59.1, 54.1, 48.5, 37.9,
N-Benzyl-6-anti-azido-5-anti-fluoro-2-azabicyclo[2.1.1]hexane
(34). Method A (DMF). Sodium azide (144 mg, 2.22 mmol) and
tetrabutylammonium chloride (30 mg) were added to a solution
of fluorobromide 11 (200 mg, 0.740 mmol) in dry DMF (15 mL)
under argon. The reaction mixture was maintained at 70 ꢀC for
5 days. Workup and flash chromatography (1:4 ether/hexanes)
afforded 74 mg (43%) (62% BORSM) of fluoroazide 34 as an oil
3
3
0.1; HRMS m/z 300.0243, calcd for C12
00.0244.
N-Benzyl-6-anti-acetoxy-5-anti-fluoro-2-azabicyclo[2.1.1]hexane
H
15IN (M þ H)
(32a). Method A (DMF). To a solution of bromofluoride 11
(900 mg, 3.33 mmol) in DMF (55 mL) under argon was added
cesium acetate (1279 mg, 6.66 mmol). The solution was maintained
at 70 ꢀC for 5 days. The usual workup and flash chromatography
at R
f
= 0.59 (1:1 ether/hexanes) and 62 mg (31%) of starting
1
material 11 at R =0.69; after two column separations, for 34: H
(1:3 ether/hexanes) afforded 578 mg (64%) of unreacted fluoro-
bromide 11 at R =0.61 (1:1 ether/hexane) and 249 mg (30%) (84%
f
NMR (400 MHz, CDCl ) δ 7.35-7.27 (m, 5H), 5.21 (dd, J=
f
3
1
BORSM) of fluoroacetate 32a at R =0.44 (1:1 ether/hexanes); H
60.9, 7.1 Hz, 1H, H ), 4.31 (dd, J=7.1, 2.9 Hz, 1H, H ), 3.85 (d,
f
5
6
NMR (400 MHz, CDCl
ABX pattern, 2H, H and H
d, J=13.2, Hz, 1H), 3.82 (d, J=13.2, Hz, 1H), 3.48 (dd, J=7.1, 2.2
Hz, 1H, H ), 3.05-2.95 (m, 2H, H ), 2.88 (ddd, J=9.0, 3.7,
), 2.12 (s, 3H); H NMR (400 MHz, CDCl /C
:1 mixture) δ7.41-7.22(m, 5H), 5.26-4.99 (m, ABX pattern, 2H,
3
) δ 7.38-7.22 (m, 5H), 5.29-5.08 (m,
6
J=13.1, 1H), 3.79 (d, J=13.2, 1H), 3.43 (dd, J=7.1, 2.0 Hz, 1H,
), 3.00 (dt, J=9.0, 1.3 Hz, 1H, H ), 2.96 (ddt, J=7.1, 4.7, 1.2
Hz, 1H, H ), 2.85 (ddd, J=9.1, 3.7, 1.2 Hz, 1H, H ); C NMR
0
3
5
) (see Supporting Information), 3.88
H
1
3
1
3
(
4
1
3
þ H
4
3
(100 MHz, CDCl ) δ 138.0, 128.5, 128.4 and 127.4, 99.6 (JC,F=
1
1
1
.2 Hz, 1H, H
3
3
6
D
6
220.2 Hz, C ), 67.7 (JC,F=4.2 Hz), 66.3 (JC,F=18.1 Hz), 58.7,
5
1
52.1 (JC,F=7.1 Hz), 48.4 (JC,F=17.3 Hz); F NMR (282 MHz,
9
H and H ), 3.73 (d, J=13.2, Hz, 1H), 3.66 (d, J=13.2, Hz, 1H),
CDCl ) δ -216.11 (d, J=60.4 Hz); HRMS m/z 233.1202, calcd
5
6
3
3
.48 (dd, J=7.1, 2.2 Hz, 1H, H ), 2.86 (t, J=6.0 Hz, 1H, H
1
4
),
for C12
H
14FN
4
(M þ H) 233.1202.
J. Org. Chem. Vol. 74, No. 21, 2009 8241

Krow et al.
JOCArticle
N-Benzyl-6-anti-amino-5-anti-fluoro-2-azabicyclo[2.1.1]hexane
N-Benzyl-5-anti-fluoro-6-anti-phenylthio-2-azabicyclo[2.1.1]hexane
(37). According to method B, to a solution of bromofluoride
11 (26 mg, 0.096 mmol) in dry DMSO (0.6 mL) was added
NaSPh (38 mg, 0.289 mmol), and the reaction mixture was
maintained at 60 ꢀC for 9 days under argon. The usual workup
and chromatography (prep TLC, 1:3 ether/hexanes) afforded
=0.26 (1:3 ether/
hexanes) as a light orange-colored oil; H NMR (400 MHz,
CDCl ) δ 7.36-7.18 (br, 10H), 5.13 (dd, J=61.8, 6.7 Hz, 1H,
), 3.81 (d, J=
(
35). To a solution of fluoroazide 34 (70 mg, 0.301 mmol) in
toluene (20 mL) and water (2.5 mL) was added triphenyl-
phosphine (166 mg, 0.633 mmol). The reaction mixture was
heated to 60 ꢀC for 5 h. After cooling to rt the organic layer
was separated, and the aqueous layer was extracted with
methylene chloride (2 ꢀ 5 mL). The combined organic layers
were dried over Na SO . Filtration, removal of solvent, and
fluoro(phenylthio) ether 37 (20 mg, 69%) at R
f
1
2
4
purification by flash chromatography (1-10% methanol in
methylene chloride) afforded 53 mg (85%) of fluoroamine 35 at
R = 0.40 (1:9 MeOH/CH Cl ); H NMR (400 MHz, CDCl )
3
H
5
), 3.88 (d, J=13.2 Hz, 1H), 3.88-3.84 (m, 1H, H
6
1
13.2 Hz, 1H), 3.54 (dd, J=6.8, 2.1 Hz, 1H, H ), 3.11 (dt, J=9.0,
1.2 Hz, 1H, H ), 3.01 (m, 1H, H ), 2.78 (ddd, J=9.0, 3.9, 1.2 Hz,
0
1H, H ); C NMR (100 MHz, CDCl ) δ 138.2, 129.1, 129.0,
3 3
f
2
2
3
1
δ 7.40-7.23 (m, 5H), 5.27 (dd, J=62.3, 7.4 Hz, 1H, H ), 3.83 (d,
5
3
4
1
3
J=13.3, 1H), 3.78 (d, J=13.3, 1H), 3.73 (dd, J=7.5, 1.3 Hz, 1H,
H
6
), 3.20 (dd, J=7.0, 2.1 Hz, 1H, H
1
), 2.89-2.83 (m, 2H, H
3
),
C
128.5, 128.4, 127.3, 126.1, 99.9 (d, J=216.4 Hz), 68.5 (d, J=18.7
Hz), 59.9, 54.6 (d, J=4.6 Hz), 53.6 (d, J=6.4 Hz), 50.3 (d, J=
1
3
2
.68 (ddt, J=7.1, 5.2, 1.2 Hz, 1H, H ), 2.20 (br s, 2H, NH );
4
2
1
17.0 Hz); F NMR (282 Hz, CDCl
9
NMR (100 MHz, CDCl
C,F=212.1 Hz, C ), 67.7 (JC,F=16.2 Hz), 63.8 (JC,F=2.1 Hz),
8.8, 52.9 (JC,F = 8.2 Hz), 50.3 (JC,F = 16.3 Hz); F NMR
282 MHz, CDCl ) δ -213.55 (brd, J = 63.1 Hz); HRMS
3
) δ 138.6, 128.4, 128.2 and 127.0, 101.9
3
) δ -210.2 (d, J=62.4 Hz);
19FNS (M þ H) 300.1217.
(
J
5
HRMS m/z 300.1226 calcd for C18H
1
9
5
(
3
Acknowledgment. The authors acknowledge the National
Science Foundation for funding (CHE 0515635) and thank
Alex Shaffer for assistance and Hans Reich and David
Dalton for helpful discussions.
m/z 207.1301, calcd for C12
H
16FN
2
(M þ H) 207.1298.
N-Benzyl-6-anti-acetamido-5-anti-fluoro-2-azabicyclo[2.1.1]hexane
36). DMAP (44 mg, 0.3636 mmol) was added to the solution of
fluoroamine 35 (25 mg, 0.1212 mmol) in dry methylene chloride
(
(
3 mL) under argon. The resulting solution was cooled to 0 ꢀC, and
acetyl chloride (26 μL, 0.3636) was added dropwise. The reaction
mixture was allowed to rt and stirred for 3 h. The reaction mixture
Supporting Information Available: General experimental
procedures; control reactions with dibromide 13; reactions in
DMSO to prepare 16a, 18, 19, 20, 24a, 27, 32a, and 34; reac-
tion with BAST to prepare 26 and attempted preparation
of 26 using AgF/DMF; variance of PhSNa concentrations
(Table S-5) with monobromide 10 to give thioether 30; compar-
ison of reactivities for reaction of bromides 9, 10, 11, and 23 with
PhSNa (Table 6); proposed mechanisms for formation of alde-
wasthendilutedwithCH
and dried over Na SO . Filtration, removal of solvent and purifica-
tion by preparative thin layer chromatography (1:9 MeOH/CH Cl
afforded 19 mg (63%) of fluoroacetamide 36 at R=0.54(1:9MeOH/
2
Cl
2
(7 mL), washed with water (3 ꢀ 5mL),
2
4
2
2
)
f
1
CH
br s, 1H, NH), 5.34 (dd, J=62.5, 7.4 Hz, 1H, H
.4, 1.8 Hz, 1H, H ), 3.91 (d, J = 13.2, 1H), 3.84 (d,
J=13.2, 1H), 3.33 (dd, J=7.1, 2.5 Hz, 1H, H ), 3.07 (br d, J=
2
Cl
2
); H NMR (400 MHz, CDCl
3
) δ 7.41-7.22 (m, 5H), 6.54
(
5
), 4.79 (ddd, J=9.3,
1
7
6
hyde 19, X-ray diffraction analysis of dibromide 9; copies of H
1
3
19
NMR, C NMR, and F NMR for new compounds; a
calculated spectrum for N-methyl-6-anti-fluoro-5-anti-hydro-
xy-2-azabicyclo[2.1.1]hexane 32c; SCF Energies and coordi-
nates of optimized geometries for amine invertomers of
bromides 9-11 shown in Table 4 along with pictures of orbitals
for dibromide 9; and energy minimizations of ions derived from
N-methyl-2-azabicyclo[2.1.1]hexyl-5-cations 39. This material
is available free of charge via the Internet at http://pubs.acs.org.
1
9
7
.1, Hz, 1H, H
.1, 5.7, 1.2 Hz, 1H, H
δ 170.2, 138.1, 128.6, 128.4 and 127.3, 101.8 (JC,F=209.0 Hz, C5),
7.0 (JC,F=18.6 Hz), 58.8, 58.6 (JC,F=3.2 Hz), 52.5 (JC,F=7.1 Hz),
3
), 2.85 (br dd, J=9.1, 4.1 Hz, 1H, H
3
0
), 2.78 (ddt, J=
13
4
), 2.02 (s, 3H); C NMR (100 MHz, CDCl
3
)
6
4
(
(
19
9.2 (JC,F=16.4 Hz), 23.7; F NMR (282 MHz, CDCl
brd, J=63.0 Hz); HRMS m/z 249.1414, calcd for C14
M þ H) 249.1403.
3
) δ -211.80
2
H18FN O
8
242 J. Org. Chem. Vol. 74, No. 21, 2009