Synthesis of β-fluoroamines by Lewis base catalyzed hydrofluorination of aziridines

Article abstract of DOI:10.1021/jo300433a

Lewis base catalysis promotes the in situ generation of amine-HF reagents from benzoyl fluoride and a non-nucleophilic alcohol. The hydrofluorination of aziridines to provide β-fluoroamines using this latent HF source is described. This protocol displays a broad scope with respect to aziridine substitution and N-protecting groups. Examples of regio- and diastereoselective ring opening to access medicinally relevant β-fluoroamine building blocks are presented.

Full text of DOI:10.1021/jo300433a

Note
pubs.acs.org/joc
Synthesis of β-Fluoroamines by Lewis Base Catalyzed
Hydrofluorination of Aziridines
Julia A. Kalow, Dana E. Schmitt, and Abigail G. Doyle*
Department of Chemistry, Princeton University, Princeton, New Jersey 08544, United States
S
* Supporting Information
ABSTRACT: Lewis base catalysis promotes the in situ generation of
amine-HF reagents from benzoyl fluoride and a non-nucleophilic
alcohol. The hydrofluorination of aziridines to provide β-fluoroamines
using this latent HF source is described. This protocol displays a broad
scope with respect to aziridine substitution and N-protecting groups.
Examples of regio- and diastereoselective ring opening to access
medicinally relevant β-fluoroamine building blocks are presented.
ince the initial report of pyridinium poly(hydrogen
S
fluoride) (PPHF) by Bergstrom et al. in 1963,1 amine-
HF reagents have become commonplace in synthetic organic
chemistry as an alternative to anhydrous HF.2 Although Olah
and co-workers developed a wide range of C−F bond-forming
reactions using PPHF in the 1970s,3 in modern laboratories,
this reagent and the milder Et3N-3HF4 are primarily used for
silyl ether deprotections.5 Given the significant interest in new
methods for the preparation of organofluorine compounds, it is
surprising that these reagents have not experienced greater
development in recent years. Presumably, this is in part due to
the limited number of commercially available amine-HF
reagents, which are prepared using anhydrous HF, and the
requirement for a large excess of HF (>20 equiv) relative to
substrate,3 as well as their corrosiveness and functional group
incompatibility.
Figure 1. β-Fluoroamine-containing bioactive targets.
affinity offered by drugs containing C−F bonds, β-fluoro
substitution lowers the pKa of amines, which in turn improves
bioavailability and increases blood-brain barrier penetration.10
Because of the utility of β-fluoroamines, the past decade has
witnessed the development of many new methods for their
synthesis. Many of these strategies rely on the electrophilic
fluorination of carbonyl-containing compounds or imines and
require further elaboration to provide the desired β-fluoro-
amine.11 In contrast, aziridine ring-opening by fluoride offers a
direct route to β-fluoroamines. Although methods using metal
or tetraalkylammonium fluoride salts have been developed,
these reactions are effective only with activated aziridines (e.g.,
N-tosyl).12 The seminal studies of Wade13 and Laurent14
demonstrated that anhydrous HF and amine-HF reagents effect
the hydrofluorination of simple unactivated aziridines. How-
ever, the reactions often afford stereoisomeric mixtures of
products and suffer from acid-promoted side reactions.
We chose to evaluate our catalytic hydrofluorination
conditions for the ring opening of Boc-protected cyclohexene
imine 1a, an acid-sensitive substrate that is not stable to PPHF.
Gratifyingly, the desired β-fluoroamine 2a was formed in 93%
yield within 15 min (Table 1, entry 1). These conditions are
mild (50 °C), require only 2 equiv of the fluorinating reagent
PhCOF, and are performed at high concentrations (1 M) in a
green solvent (tert-butyl methyl ether, TBME). A control
In the context of developing an asymmetric fluoride ring-
opening reaction of epoxides, we anticipated that the solvolysis
of an acid fluoride catalyzed by a Lewis base, such as 1,5-
diazabicyclo[4.3.0]non-5-ene (DBN), would generate an
amine-HF reagent in situ. We recognized that this strategy
could prove of significant practical utility, overcoming many of
the traditional challenges associated with this class of reagents.
Indeed, the combination of PhCOF and 1,1,1,3,3,3-hexafluor-
oisopropanol (HFIP) serves as a synthetically useful latent
source of HF and effects enantioselective ring opening in the
presence of a chiral Lewis acid cocatalyst.6 Detailed mechanistic
studies, however, demonstrated that the catalytically relevant
nucleophile in these epoxide-opening reactions was a transition-
metal fluoride, not an amine-HF species.7 Nevertheless, the
catalytic generation of an amine-HF reagent for hydro-
fluorination remains an intriguing goal. In this note, we
demonstrate the successful application of this strategy to a
practical and general synthesis of β-fluoroamines by aziridine
hydrofluorination.
The β-fluoroamine motif is of great importance in medicinal
chemistry,8 occurring in numerous drug candidates (Figure 1).9
In addition to the improved metabolic stability and binding
Received: February 29, 2012
Published: April 10, 2012
© 2012 American Chemical Society
4177
dx.doi.org/10.1021/jo300433a | J. Org. Chem. 2012, 77, 4177−4183

The Journal of Organic Chemistry
Note
a
a
Table 1. Reaction Development
Table 2. Substrate Scope: N-Substitution
b
b
entry
variation from standard conditions
none
conv. (%) yield (%)
1
2
3
4
5
6
100
20
98
75
81
35
93
6
without DBN
in glass vial
89
68
79
30
with TFE instead of HFIP
1.1 equiv of PhCOF, 2.2 equiv of HFIP
at 24 °C
a
Reaction conditions: 1a (0.25 mmol), DBN (0.05 mmol), PhCOF
(0.5 mmol), HFIP (1 mmol), and TBME (0.25 mL), 50 °C, sealed
b
polypropylene vial, 15 min. Determined by GC using dodecane as a
quantitative internal standard.
reaction demonstrated that the DBN catalyst is required for
productive reactivity, although minimal background reaction
was observed in its absence (entry 2). While optimal results
were observed in a polypropylene reaction vessel, the reaction
proceeded nearly as efficiently in glass (entry 3). The more
inexpensive proton source 2,2,2-trifluoroethanol (TFE) pro-
vided lower reactivity, but the yield of product remained high
(entry 4). Lower equivalents of PhCOF may also be employed
at the expense of reaction rate (entry 5), and the hydro-
fluorination was significantly slower when performed at room
temperature (entry 6). After a 1 h reaction time, the
hydrofluorinations in entries 3 and 4 proceed to full conversion
with >90% yield.
Notably, the hydrofluorination of 1a may be performed on a
gram scale in a standard glass round-bottom flask, without
exclusion of air or moisture. Quenching the reaction after 1 h
with methanolic ammonia, followed by aqueous workup,
allowed isolation of the fluoroamine 2a in 92% yield without
column chromatography (Table 2, entry 1).
a
Reaction conditions: aziridine (1 equiv), DBN (0.2 equiv), PhCOF
(2 equiv), and HFIP (4 equiv) in TBME (1 M based on aziridine), 50
b
°C, sealed polypropylene vial. Isolated yield; average of two
c
experiments on a 0.5−1 mmol scale. Reaction was performed with
d
1a (1 g, 5.07 mmol) in a glass round-bottom flask. 95% purity (1H
e
f
NMR). 0.5 M in cyclopentyl methyl ether (CPME). Accompanied by
24% isolated yield of oxazoline byproduct. Accompanied by 48%
isolated yield of unreacted 1k.
The scope of the catalytic hydrofluorination with respect to
the N-substituent of the aziridine was next investigated. Because
the reaction of amine-HF with glass competes with ring
opening and the aziridines displayed variable reactivity, the
hydrofluorinations were performed in polypropylene reaction
vessels to standardize the reaction protocol.15 Commonly
employed protecting groups were tolerated in addition to Boc,
including Cbz (Table 2, entry 2) and Bn (entry 3). N-Alkyl
aziridines, such as 1c, are sufficiently basic that hydro-
fluorination occurs in the absence of DBN. N-Aryl and
heteroaryl aziridines are readily synthesized from aryl bromides
and N−H aziridines using conditions developed by Yudin16 and
also provided β-fluoroamines in good yield (entries 4 and 5).
An aziridine functionalized with caffeine, which contains several
potentially problematic Lewis basic sites, required extended
reaction times due in part to its minimal solubility in organic
solvents, but afforded product 2f in high yield (entry 6). Acyl
aziridines, including those derived from picolinic and 4-
thiazolecarboxylic acid, provided β-fluoroamides with minimal
production of the oxazoline derived from acid-catalyzed
rearrangement14 (entries 7−10). However, N-tosyl aziridine
1k reacted sluggishly, highlighting the complementarity of this
hydrofluorination method to ring-opening protocols by metal
fluorides (entry 11). In all cases, solely the trans-β-fluoroamine
g
and 19F NMR spectra to known compounds.12 This is
important in a medicinal-chemistry context: the relative
configuration of vicinal amine and fluoride substituents is
known to influence binding potency and bioavailability.8,10
Additionally, the standard reaction conditions effect the
hydrofluorination of other cyclic and acyclic meso aziridines in
high yield. The fluorination of an unsaturated eight-membered
ring fused aziridine (5) provided 6 as the only fluorinated
product (Table 3, entry 2). An acyclic N-Fmoc aziridine (7)
underwent hydrofluorination in good yield, despite the
sensitivity of this protecting group to basic conditions, and
provided the product as a single diastereomer (8, entry 3). This
protocol enables the synthesis of useful heterocyclic building
blocks, such as the β-fluoroamine-substituted pyrrolidine 10
(entry 4). However, a significant limitation remains the
laborious synthesis of functionalized aziridines, which are
accessed in three or more steps from the corresponding
epoxide or alkene.
Next, we chose to evaluate unsymmetrically substituted
aziridines. 2-Carboxymethyl N-Boc aziridine 11, which may be
synthesized in enantioenriched form by an organocatalytic
1
product was observed, as determined by comparison of the H
4178
dx.doi.org/10.1021/jo300433a | J. Org. Chem. 2012, 77, 4177−4183

The Journal of Organic Chemistry
Note
a
species in this catalytic hydrofluorination protocol is a
DBN·(HF)4 adduct,6 2a is produced in <15% ee when chiral
amine catalysts are used (see the Supporting Information).
However, the flexibility of the method with respect to N-
substitution offers the opportunity to achieve asymmetric
induction with a chiral auxiliary.
Table 3. Substrate Scope: Backbone Substitution
We selected aziridine 15, derived from inexpensive (S)-1-
phenylethylamine in two steps, as a model substrate for
diastereoselective hydrofluorination (Scheme 2). This aziridine
a
Scheme 2. Diastereoselective Hydrofluorination of 15
a
a
b
Reagents and conditions: (a) 1. LiClO4, MeCN, reflux, 40 h; 2. MsCl,
Reaction conditions: see Table 2. Isolated yield; average of two
c
Et3N-CH2Cl2, 0 °C−rt, 24 h; (b) cat. DBN, PhCOF, HFIP, TBME, 50
°C, 18 h; (c) cat. Pd(OH)2/C, 1 atm H2, Boc2O, EtOH, rt, 8 h.
experiments on a 0.5−1 mmol scale. 92% purity (LC).
protocol,17 gave N-Boc-O-Me β-fluoro-α-amino acid 12 under
the standard reaction conditions, albeit with an extended
reaction time (Scheme 1, eq 1). The hydrofluorination
has been used for the synthesis of chiral ligands and
organocatalysts and provides modest diastereoselectivity in
ring-opening reactions with a variety of heteroatomic
nucleophiles.21 Under our standard catalytic conditions, the
ring opening of 15 proceeded smoothly to provide a mixture of
fluoroamine (1S,2S) and (1R,2R) diastereomers with modest
selectivity (2.4:1 dr; for additional chiral auxiliaries and reaction
conditions, see the Supporting Information). Alternative
sources of HF provided poor reactivity in the hydrofluorination
of 15, which is considered an unactivated aziridine.22
These diastereomers could be separated by standard column
chromatography on SiO2, providing the major diastereomer
(1S,2S,1′S)-16 in 60% isolated yield and >30:1 dr, as judged by
19F NMR.23 The observed sense of diastereoinduction is
consistent with literature precedent.21 Furthermore, the chiral
auxiliary was readily cleaved by hydrogenolysis in the presence
of Boc2O to provide (S,S)-2a in 98% yield and 99% ee. This
procedure provides enantioenriched fluoroamine in 44% overall
yield from commercial materials, a significant improvement
over previous approaches.
Scheme 1. Regioselective Hydrofluorination for the
Preparation of Medicinally Relevant Building Blocks
proceeds with excellent diastereoselectivity and no erosion of
ee. Consistent with literature precedent,13,14 the reaction is also
regioselective, with fluorination occurring at the carbon that
best stabilizes a positive charge. This synthetic sequence
provides efficient access to enantioenriched fluorinated amino
acids in three steps from readily available α,β-unsaturated
aldehydes.17
The orthogonally protected piperidine aziridine 13 repre-
sents a common intermediate in the synthesis of medicinal
chemistry targets.18 Indeed, hydrofluorination of 13 provides a
β-fluoroamine that can be found in several patents (Figure 1);
however, existing syntheses suffer from high step count,
inconvenient protecting group manipulations, and low yields
in the C−F bond-forming reaction.9b,19 We were pleased to
find that under the standard conditions, aziridine 13 delivers 4-
fluoro-3-aminopiperidine 14 in 76% isolated yield, as an 11:1
ratio of regioisomers (Scheme 1, eq 2).
In conclusion, we anticipate that this practical method will
provide access to useful quantities of versatile β-fluoroamine
building blocks.
EXPERIMENTAL SECTION
■
General Experimental Methods. Hydrofluorinations were
performed in 8 mL polypropylene tubes and sealed with caps fitted
with rubber O-rings. Column chromatography was performed with
silica gel (40−53 μm, 60 Å). 1,5-Diazabicyclo[4.3.0]non-5-ene was
distilled from CaH2 and stored over activated 3 Å molecular sieves.
Benzoyl fluoride was filtered through SiO2, eluting with pentanes, and
solvent was removed in vacuo. It was stored in a plastic vial in a
desiccator containing CaSO4.
7-Azabicyclo[4.1.0]heptane,24 (Z)-9-azabicyclo[6.1.0]non-4-ene,25
cis-2,3-dibutylaziridine,26 benzyl 3,6-diazabicyclo[3.1.0]hexane-3-car-
boxylate,27 8-bromocaffeine,28 1a,29 1b,30 1c,31 1d−1f,16 1g,34 1j,32
1k,33 3,34 11,17 13,18 and 1535 were prepared according to literature
procedures.
Despite significant recent advances in the field of asymmetric
fluorination,20 the synthesis of enantioenriched cyclic trans-
fluoroamines still relies on chiral chromatography and suffers
from poor overall yields (typically <3%).11d As expected based
on preliminary experiments suggesting that the nucleophilic
General Procedure for Boc Protection. To a 0.67 M solution of
N−H aziridine (1 equiv), DMAP (0.05 equiv), and triethylamine (2.5
equiv) in anhydrous CH2Cl2 cooled to 0 °C under N2 was added
4179
dx.doi.org/10.1021/jo300433a | J. Org. Chem. 2012, 77, 4177−4183

The Journal of Organic Chemistry
Note
1
Boc2O (2.5 equiv), and the solution was warmed to rt. Upon
completion, the reaction was concentrated and purified by column
chromatography.
1450, 1280, 1222, 1089; H NMR (500 MHz, CDCl3) δ 7.77 (d, J =
7.5 Hz, 2H), 7.63 (d, J = 7.5 Hz, 2H), 7.41 (t, J = 7.4 Hz, 2H), 7.32 (t,
J = 7.4 Hz, 2H), 4.45 (d, J = 6.6 Hz, 2H), 4.23 (t, J = 6.5 Hz, 1H), 2.31
(s, 2H), 1.52−1.33 (m, 12H), 0.92 (t, J = 6.8 Hz, 6H); 13C NMR (125
MHz, CDCl3) δ 164.2, 143.9 (2C), 141.5 (2C), 127.9 (2C), 127.2
(2C), 125.2 (2C), 120.1 (2C), 67.8, 47.2, 43.0 (2C), 29.8 (2C), 27.5
(2C), 22.6 (2C), 14.2 (2C); HRMS (ESI+) calculated for C25H32NO2
([M + H]+), 378.2428; found, 378.2428.
General Procedure for Acylation. To a 0.2 M solution of N−H
aziridine (1 equiv) in anhydrous CH2Cl2 at rt under N2 was added 4-
dimethylaminopyridine (1.1 equiv), N,N′-dicyclohexylcarbodiimide
(1.1 equiv), and the appropriate carboxylic acid (1 equiv). The
reaction was stirred for 12−24 h, and upon completion, the suspension
was diluted with hexanes, filtered, and concentrated. The crude
reaction was purified by column chromatography (5−40% EtOAc-
hexanes with 0.5% Et3N).
3-Benzyl 6-tert-Butyl-3,6-diazabicyclo[3.1.0]hexane-3,6-di-
carboxylate (9). Prepared from benzyl 3,6-diazabicyclo[3.1.0]-
hexane-3-carboxylate according to the general procedure for Boc-
protection (7−60% EtOAc-hexanes) to provide the title compound as
an off-white solid in 94% yield (1.20 g). FTIR (thin film, cm−1) 3977,
7-(2-Methoxyphenyl)-7-azabicyclo[4.1.0]heptane (1e):16
0.390 g, 96% yield; FTIR (thin film, cm−1) 2993, 2933, 2855, 1593,
1496, 1438, 1410, 1266, 1231, 1117, 1030; 1H NMR (500 MHz,
CDCl3) δ 6.97−6.74 (m, 4H), 3.86 (s, 3H), 2.23 (s, 2H), 2.14−2.05
(m, 2H), 1.94−1.82 (m, 2H), 1.56−1.44 (m, 2H), 1.37−1.22 (m, 2H);
13C NMR (125 MHz, CDCl3) δ 152.9, 144.11, 122.4, 120.6, 120.3,
1
2877, 1702, 1421, 1314, 1145, 1115; H NMR (500 MHz, CDCl3) δ
7.37−7.27 (m, 5H), 5.11 (d, J = 12.3 Hz, 1H), 5.03 (d, J = 12.4 Hz,
1H), 4.08 (d, J = 12.0 Hz, 2H), 3.34 (t, J = 11.1 Hz, 2H), 3.07 (d, J =
1.3 Hz, 2H), 1.39 (s, 9H); 13C NMR (125 MHz, CDCl3) δ 158.4,
154.9, 136.4, 128.6 (2C), 128.2, 128.2 (2C), 81.9, 67.2, 45.4, 44.9,
39.8, 39.6, 27.9 (3C); HRMS (ESI+) calculated for C17H22N2NaO4
([M + Na]+), 341.1472; found, 341.1467.
General Procedure for Hydrofluorination on 1 mmol Scale.
In an 8 mL polypropylene tube, the aziridine (1 mmol, 1 equiv) was
dissolved or suspended in TBME (1 mL). 1,5-Diazabicyclo(4.3.0)non-
5-ene (24.7 μL, 0.2 mmol, 0.2 equiv) was charged, followed by HFIP
(0.42 mL, 4 mmol, 4 equiv) and PhCOF (0.22 mL, 2 mmol, 2 equiv).
The tube was sealed, placed in an aluminum heating block preheated
to 50 °C, and stirred for the designated time. Unless otherwise
specified, the reaction was quenched with saturated aqueous NaHCO3
and extracted with EtOAc (3×). The combined organic extracts were
dried over MgSO4, filtered, and concentrated. The crude material was
purified by column chromatography (5−40% EtOAc-hexanes).
Hazard Note. Caution! HF is generated in these reactions; while
less corrosive than PPHF or anhydrous HF, avoid all contact with skin
and quench carefully.
110.8, 55.6, 39.4 (2C), 24.4 (2C), 20.6 (2C); HRMS (ESI+)
calculated for C13H18NO ([M + H)+), 204.1383; found, 204.1392.
8-(7-Azabicyclo[4.1.0]heptan-7-yl)-1,3,7-trimethyl-1H-pu-
rine-2,6(3H,7H)-dione (1f):16 0.614 g, 85% yield; FTIR (thin film,
1
cm−1) 2938, 2860, 1652, 1698, 1499, 1433; H NMR (500 MHz,
CDCl3) δ 3.85 (s, 3H), 3.49 (s, 3H), 3.38 (s, 3H), 2.87−2.82 (m, 2H),
2.09−2.01 (m, 2H), 1.99−1.91 (m, 2H), 1.57−1.48 (m, 2H), 1.38−
1.30 (m, 2H); 13C NMR (125 MHz, CDCl3) δ 158.0, 154.9, 151.9,
147.0, 105.5, 41.4 (2C), 31.0, 29.8, 27.9, 24.0 (2C), 20.0 (2C); HRMS
(ESI+) calculated for C14H20N5O2 ([M + H]+), 290.1612; found,
290.1609.
7-Azabicyclo[4.1.0]heptan-7-yl(pyridin-2-yl)methanone
(1h). Prepared from 7-azabicyclo[4.1.0]heptane and picolinic acid
according to the general procedure for aziridine acylation and isolated
as a white solid in 72% yield (0.731 g). FTIR (thin film, cm−1) 2935,
1
1670, 1585, 1440, 1417, 1323, 1137; H NMR (500 MHz, CDCl3) δ
8.70 (d, J = 4.6 Hz, 1H), 8.08 (d, J = 7.8 Hz, 1H), 7.81 (t, J = 7.7 Hz,
1H), 7.42 (dd, J = 7.4, 4.8 Hz, 1H), 2.86 (d, J = 2.9 Hz, 2H), 2.29−
2.10 (m, 2H), 1.96−1.80 (m, 2H), 1.59− 1.49 (m, 2H), 1.40−1.29 (m,
2H); 13C NMR (125 MHz, CDCl3) δ 177.9, 151.2, 149.6, 136.8,
126.4, 124.1, 37.5 (2C), 23.9 (2C), 20.2 (2C); HRMS (ESI+)
calculated for C12H15N2O ([M + H]+), 203.1179; found, 203.1179.
7-Azabicyclo[4.1.0]heptan-7-yl(thiazol-4-yl)methanone (1i).
Prepared from 7-azabicyclo[4.1.0]heptane and 4-thiazolecarboxylic
acid according to the general procedure for aziridine acylation and
isolated as a white solid in 82% yield (0.683 g). FTIR (thin film, cm−1)
3092, 2930, 2854, 1647, 1489, 1419, 1297; 1H NMR (300 MHz,
CDCl3) δ 8.82 (d, J = 2.1 Hz, 1H), 8.19 (d, J = 2.1 Hz, 1H), 2.91−2.85
(m, 2H), 2.23−2.10 (m, 2H), 1.92 (td, J = 8.8, 4.3 Hz, 2H), 1.62−1.47
(m, 2H), 1.42−1.27 (m, 2H); 13C NMR (125 MHz, CDCl3) δ 173.3,
153.0, 152.0, 125.9, 37.6 (2C), 24.0 (2C), 20.2 (2C); HRMS (ESI+)
calculated for C10H13N2OS ([M + H]+), 209.0743; found, 209.0743.
(Z)-tert-Butyl 9-Azabicyclo[6.1.0]non-4-ene-9-carboxylate
(5). Prepared from (Z)-9-azabicyclo[6.1.0]non-4-ene according to
the general procedure for Boc-protection (1−10% acetone-hexanes)
and isolated as a yellow oil in 50% yield (1.00 g). FTIR (thin film,
cm−1) 3357, 2978, 2933, 1714, 1441, 1367, 1298, 1244, 1154, 1088;
1H NMR (500 MHz, CDCl3) δ 5.61−5.52 (m, 2H), 2.51−2.33 (m,
tert-Butyl (trans-2-Fluorocyclohexyl)carbamate (2a). The
general procedure was performed in a 50 mL glass round-bottom
flask with 1a (1 g, 5.07 mmol), and quenched with 25 mL of 7 M
methanolic NH3. After 3 h, the reaction mixture was poured into 1 M
aqueous NaOH (100 mL) and diluted with 20% Et2O-hexanes (35
mL). The organic layer was washed with 1 M NaOH (2×), and the
aqueous layer was extracted with 20% Et2O-hexanes (15 mL). The
combined organic extracts were stirred vigorously over MgSO4 and
SiO2, filtered, and concentrated. The title product was obtained as a
white solid (1.01 g, 4.65 mmol, 92% yield; 1.01 g, 4.65 mmol, 92%
yield). FTIR (thin film, cm−1) 3334, 2939, 2866, 1684, 1520, 1365,
1
1321, 1254, 1164, 1010; H NMR (500 MHz, CDCl3) δ 4.58 (br s,
1H), 4.20 (dddd, J = 50.3, 9.8, 9.8, 4.5 Hz, 1H), 3.66−3.50 (m, 1H),
2.17−2.01 (m, 2H), 1.81−1.70 (m, 1H), 1.65−1.47 (m, 2H), 1.44 (s,
9H), 1.36−1.11 (m, 3H); 13C NMR (125 MHz, CDCl3) δ 155.7, 93.6
(d, J = 178.5 Hz), 79.6, 53.9 (d, J = 18.1 Hz), 31.3, 31.2 (d, J = 5.5
Hz), 28.5 (3C), 23.9, 23.4 (d, J = 10.1 Hz); 19F NMR (282 MHz,
CDCl3) δ −179.1 (d, J = 49.0 Hz); HRMS (ESI+) calculated for
C11H20FNNaO2 ([M + Na]+), 240.1370; found, 240.1377.
Benzyl (trans-2-Fluorocyclohexyl)carbamate (2b): White solid
(211 mg, 0.84 mmol, 84% yield; 202 mg, 0.8 mmol, 80% yield); FTIR
(thin film, cm−1) 3325, 2941, 2864, 1695, 1533, 1454, 1318, 1257,
1232, 1053, 1021; 1H NMR (500 MHz, CDCl3) δ 7.36−7.28 (m, 5H),
5.20 (s, 1H), 5.14−5.04 (m, 2H), 4.22 (dm, JHF = 50.3 Hz, 1H), 3.66
(s, 1H), 2.07 (s, 2H), 1.74 (d, J = 10.2 Hz, 1H), 1.64−1.46 (m, 2H),
1.32−1.14 (m, 3H); 13C NMR (125 MHz, CDCl3) δ 156.1, 136.5,
128.4 (2C), 128.1, 128.0 (2C), 93.4 (d, J = 178.6 Hz), 66.6, 54.2 (d, J
= 17.6 Hz), 31.1 (d, J = 18.1 Hz), 31.0 (d, J = 3.7 Hz), 23.8, 23.2 (d, J
= 10.1 Hz); 19F NMR (282 MHz, CDCl3) δ −178.5 (d, J = 48.7 Hz);
HRMS (ESI+) calculated for C14H19FNO2 ([M + H]+), 252.1400;
found, 252.1402.
4H), 2.19−2.08 (m, 2H), 2.06−1.89 (m, 4H), 1.45 (s, 9H); 13C NMR
(125 MHz, CDCl3) δ 163.7, 129.3 (2C), 80.9, 42.1 (2C), 28.3 (2C),
28.0 (3C), 24.3 (2C); HRMS (ESI+) calculated for C13H22NO2 ([M +
H]+), 224.1645; found, 224.1649.
cis-(9H-Fluoren-9-yl)methyl 2,3-Dibutylaziridine-1-carboxy-
late (7). cis-2,3-Dibutylaziridine (0.663 g, 4.27 mmol, >50:1 dr) was
dissolved in THF−H2O (1:1, 17 mL). The biphasic solution was
cooled to 0 °C, and Na2CO3 (0.679 g, 6.4 mmol) was added, followed
by FmocCl (1.33 g, 5.12 mmol). The reaction was stirred, warming to
rt, for 22 h; then, the layers were separated and the aqueous layer was
extracted with Et2O (2×). The combined organics were washed with
brine, dried over MgSO4, filtered, and concentrated. The crude
material was purified by column chromatography (5−40% Et2O-
hexanes) to obtain the title compound as a viscous pale yellow oil
(1.59 g, 99% yield). FTIR (thin film, cm−1) 2955, 2928, 2859, 1717,
trans-N-Benzyl-2-fluorocyclohexanamine (2c). Extracted with
Et2O; chromatographed 5−60% Et2O-hexanes; clear oil (176 mg, 0.85
mmol, 85% yield; 183 mg, 0.88 mmol, 88% yield). This compound is
known.12b
4180
dx.doi.org/10.1021/jo300433a | J. Org. Chem. 2012, 77, 4177−4183

The Journal of Organic Chemistry
Note
N-(trans-2-Fluorocyclohexyl)pyridin-2-amine (2d): White
solid, 95% purity (148 mg, 0.76 mmol, 76% yield; 148 mg, 0.76
mmol, 76% yield); FTIR (thin film, cm−1) 3261, 2936, 2861, 1611,
HRMS (ESI+) calculated for C10H14FN2OS ([M + H]+), 229.0811;
found, 229.0810.
N-(trans-2-Fluorocyclohexyl)-4-nitrobenzamide (2j). Chroma-
tographed 5−40% acetone-hexanes; white solid (203 mg, 0.76 mmol,
76% yield; 0.85 mmol scale: 191 mg, 0.72 mmol, 84% yield). FTIR
(thin film, cm−1) 3290, 2931, 2864, 1637, 1548, 1520, 1338, 1029,
694; 1H NMR (500 MHz, CDCl3) δ 8.29 (d, J = 8.7 Hz, 2H), 7.94 (d,
J = 8.6 Hz, 2H), 6.18 (d, J = 6.2 Hz, 1H), 4.40 (dddd, J = 24.7, 10.2,
10.2, 4.6 Hz, 1H), 4.17−4.09 (m, 1H), 2.31−2.16 (m, 2H), 1.86 (d, J
= 12.7 Hz, 1H), 1.73 (d, J = 11.4 Hz, 1H), 1.69−1.60 (m, 1H), 1.46−
1.29 (m, 3H); 13C NMR (125 MHz, CDCl3) δ 165.6, 149.7, 140.4,
128.3 (2C), 124.0 (2C), 93.5 (d, J = 179.7 Hz), 54.1 (d, J = 17.4 Hz),
31.6 (d, J = 17.4 Hz), 31.1 (d, J = 5.6 Hz), 24.0 (d, J = 1.6 Hz), 23.6
(d, J = 10.5 Hz); 19F NMR (282 MHz, CDCl3) δ −178.5 (d, J = 50.9
Hz); HRMS (ESI+) calculated for C13H16FN2O3 ([M + H]+),
267.1145; found, 267.1129.
1
1524, 1487, 1419, 1029; H NMR (500 MHz, CDCl3) δ 8.08−8.06
(m, 1H), 7.42−7.37 (m, 1H), 6.59−6.54 (m, 1H), 6.46 (d, J = 8.4 Hz,
1H), 4.52 (d, J = 6.0 Hz, 1H), 4.36 (dddd, J = 50.0, 9.4, 9.4, 4.4 Hz,
1H), 3.82−3.73 (m, 1H), 2.24−2.08 (m, 2H), 1.80 (dd, J = 8.7, 3.6
Hz, 1H), 1.71−1.58 (m, 2H), 1.46−1.20 (m, 3H); 13C NMR (125
MHz, CDCl3) δ 158.5, 148.2, 137.5, 113.2, 107.4 (d, J = 1.2 Hz), 94.8
(d, J = 177.7 Hz), 54.5 (d, J = 18.0 Hz), 31.2, 31.1 (d, J = 14.1 Hz),
23.8, 23.3 (d, J = 9.8 Hz); 19F NMR (282 MHz, CDCl3) δ −177.9 (d, J
= 51.0 Hz); HRMS (ESI+) calculated for C11H16FN2 ([M + H]+),
195.1298; found, 195.1294.
N-(trans-2-Fluorocyclohexyl)-2-methoxyaniline (2e). Ex-
tracted with DCM; chromatographed 5−75% DCM-hexanes; white
solid (164 mg, 0.74 mmol, 74% yield; 0.92 mmol scale: 152 mg, 0.68
mmol, 74% yield). FTIR (thin film, cm−1) 3417, 2938, 2863, 1602,
N-(trans-2-Fluorocyclohexyl)-4-methylbenzenesulfonamide
(2k): White solid (115 mg, 0.42 mmol, 42% yield; 136 mg, 0.5 mmol,
50% yield). This compound is known.12b
1
1514, 1457, 1255, 1222, 1028; H NMR (500 MHz, MeOD) δ 6.78−
6.72 (m, 2H), 6.68−6.65 (m, 1H), 6.60−6.56 (m, 1H), 4.34 (dddd, J =
50.0, 9.3, 9.2, 4.4 Hz, 1H), 3.79 (s, 3H), 3.36−3.28 (m, 1H), 2.12−
2.01 (m, 2H), 1.79−1.70 (m, 1H), 1.68−1.50 (m, 2H), 1.41−1.28 (m,
2H), 1.27−1.17 (m, 1H); 13C NMR (125 MHz, MeOD) δ 148.6,
138.8, 122.2, 118.0, 112.3, 110.8, 95.9 (d, J = 177.0 Hz), 57.8 (d, J =
17.3 Hz), 56.0, 32.4 (d, J = 18.4 Hz), 32.0 (d, J = 5.2 Hz), 24.9, 24.4
(d, J = 10.1 Hz); 19F NMR (282 MHz, MeOD) δ −178.8 (d, J = 49.6
Hz); HRMS (ESI+) calculated for C13H19FNO ([M + H]+), 224.1451;
found, 224.1454.
trans-N-Benzyl-2-fluorocyclopentanamine (4): Clear oil (160
mg, 0.83 mmol, 83% yield; 156 mg, 0.81 mmol, 81% yield); FTIR
1
(thin film, cm−1) 3029, 2958, 2875, 1454, 1357, 1109; H NMR (500
MHz, CDCl3) δ 7.36−7.27 (m, 5H), 4.87 (dddd, J = 53.3, 5.5, 2.6, 2.6
Hz, 1H), 3.82 (s, 2H), 3.26 (dddd, J = 15.1, 6.5, 6.4, 2.3 Hz, 1H),
2.11−1.71 (m, 5H), 1.43−1.33 (m, 2H); 13C NMR (125 MHz,
CDCl3) δ 140.3, 128.6 (2C), 128.3 (2C), 127.2, 100.1 (d, J = 175.3
Hz), 64.5 (d, J = 23.9 Hz), 52.7, 31.6 (d, J = 21.8 Hz), 31.4 (d, J = 2.9
Hz), 21.8 (d, J = 1.9 Hz); 19F NMR (282 MHz, CDCl3) δ −175.8
(dddd, J = 54.0, 30.5, 24.1, 21.1 Hz); HRMS (ESI+) calculated for
C12H17FN ([M + H]+), 194.1345; found, 194.1340.
8-((trans-2-Fluorocyclohexyl)amino)-1,3,7-trimethyl-1H-pu-
rine-2,6(3H,7H)-dione (2f). Performed on a 0.5 mmol scale in 1 mL
CPME; quenched by diluting with Et2O and filtering; solid residues
were chromatographed 1−10% MeOH-CHCl3; white solid (143 mg,
0.46 mmol, 92% yield; 144 mg, 0.47 mmol, 93% yield). FTIR (thin
film, cm−1) 3366, 2938, 2861, 1702, 1655, 1614, 1579, 1550, 1483,
tert-Butyl (trans-(Z)-8-Fluorocyclooct-4-en-1-yl)carbamate
(6). Extracted with Et2O; chromatographed 3−30% Et2O-hexanes;
white solid (196 mg, 0.806 mmol, 81% yield; 195 mg, 0.801 mmol,
80% yield). FTIR (thin film, cm−1) 3345, 2932, 1695, 1518, 1366,
1251, 1171, 1023; 1H NMR (501 MHz, CDCl3) δ 5.72−5.58 (m, 2H),
4.70 (br s, 1H), 4.49 (ddd, J = 48.3, 6.5, 6.5 Hz, 1H), 4.02 (br s, 1H),
2.47−2.36 (m, 1H), 2.33−2.23 (m, 1H), 2.23−2.11 (m, 3H), 2.10−
1.98 (m, 1H), 1.98−1.86 (m, 1H), 1.52 (ddd, J = 14.7, 10.9, 5.7 Hz,
1H), 1.44 (s, 9H); 13C NMR (126 MHz, CDCl3) δ 155.7, 130.1,
128.7, 94.4 (d, J = 173.8 Hz), 79.5, 52.5 (d, J = 18.5 Hz), 32.0 (d, J =
22.7 Hz), 31.6 (d, J = 4.1 Hz), 28.5 (3C), 23.0, 22.3 (d, J = 9.6 Hz);
19F NMR (282 MHz, CDCl3) δ −178.9 (m); HRMS (ESI+)
1
1454, 1223, 1033; H NMR (500 MHz, CDCl3) δ 4.43 (dddd, J =
50.7, 9.9, 9.9, 4.5 Hz, 1H), 4.18 (d, J = 5.9 Hz, 1H), 3.97−3.86 (m,
1H), 3.68 (s, 3H), 3.52 (s, 3H), 3.37 (s, 3H), 2.43−2.35 (m, 1H), 2.20
(ddd, J = 12.6, 8.9, 4.0 Hz, 1H), 1.89−1.81 (m, 1H), 1.76−1.69 (m,
1H), 1.67−1.59 (m, 1H), 1.47−1.22 (m, 3H); 13C NMR (125 MHz,
CDCl3) δ 154.5, 152.8, 151.9, 148.5, 103.3, 94.0 (d, J = 178.5 Hz),
56.9 (d, J = 17.2 Hz), 31.5, 31.4 (d, J = 10.2 Hz), 29.9, 29.7, 27.8, 24.0
(d, J = 1.3 Hz), 23.6 (d, J = 10.6 Hz); 19F NMR (282 MHz, CDCl3) δ
−179.0 (d, J = 50.6 Hz) HRMS (ESI+) calculated for C14H21FN5O2
([M + H]+), 310.1674; found, 310.1683.
calculated for C13H22FNNaO2 ([M + Na]+), 266.1527; found,
266.1533.
N-(trans-2-Fluorocyclohexyl)benzamide (2g): White solid (169
mg, 0.76 mmol, 76% yield; 112 mg, 0.51 mmol, 51% yield). This
compound is known.12b
(9H-Fluoren-9-yl)methyl (trans-6-Fluorodecan-5-yl)-
carbamate (8). Performed on a 0.5 mmol scale; chromatographed
without aqueous workup, 2−20% Et2O-hexanes; white solid, 92%
purity (189 mg, 95% yield; 176 mg, 89% yield); analytically pure
product was obtained by preparatory SFC (162 mg, 0.408 mmol, 81%
yield). FTIR (thin film, cm−1) 3305, 2957, 2931, 2859, 1687, 1539,
1253, 1117, 1043; 1H NMR (300 MHz, CDCl3) δ 7.77 (d, J = 7.5 Hz,
2H), 7.60 (d, J = 7.5 Hz, 2H), 7.41 (dd, J = 7.4, 7.4 Hz, 2H), 7.32
(ddd, J = 7.3, 7.3, 1.1 Hz, 2H), 4.76 (d, J = 10.0 Hz, 1H), 4.47 (dddd, J
= 47.8, 8.5, 4.4, 1.4 Hz, 1H), 4.44 (d, J = 7.0 Hz, 2H), 4.23 (t, J = 6.8
Hz, 1H), 3.70 (dddd, J = 28.5, 8.3, 8.3, 8.3 Hz, 1H), 1.76−1.13 (m,
12H), 0.90 (t, J = 6.7 Hz, 6H); 13C NMR (125 MHz, CDCl3) δ 156.6,
144.0 (2C), 141.5 (2C), 127.8 (2C), 127.2 (2C), 125.2 (2C), 120.1
(2C), 95.5 (d, J = 171.9 Hz), 66.7, 53.6 (d, J = 18.7 Hz), 47.5, 32.5,
31.6 (d, J = 20.8 Hz), 28.2, 27.5 (d, J = 5.1 Hz), 22.7, 22.6, 14.15,
14.13; 19F NMR (282 MHz, CDCl3) δ −196.6 (ddd, J = 76.2, 38.5,
22.4 Hz); HRMS (ESI+) calculated for C25H33FNO2 ([M + H]+),
398.2490; found, 398.2483.
N-(trans-2-Fluorocyclohexyl)picolinamide (2h): White solid,
95% purity (175 mg, 0.79 mmol, 79% yield; 185 mg, 0.83 mmol, 83%
yield); FTIR (thin film, cm−1) 3366, 2940, 2864, 1663, 1519, 1025; 1H
NMR (500 MHz, CDCl3) δ 8.55 (d, J = 4.2 Hz, 1H), 8.21 (d, J = 7.8
Hz, 1H), 8.11 (d, J = 6.9 Hz, 1H), 7.85 (ddd, J = 7.7, 7.7, 1.6 Hz, 1H),
7.43 (ddd, J = 7.5, 4.7, 1.1 Hz, 1H), 4.44 (dddd, J = 50.1, 9.8, 9.7, 4.5
Hz, 1H), 4.21−4.09 (m, 1H), 2.22−2.13 (m, 2H), 1.86−1.80 (m, 1H),
1.75−1.58 (m, 2H), 1.47−1.29 (m, 3H); 13C NMR (125 MHz,
CDCl3) δ 164.2, 149.9, 148.1, 137.5, 126.3, 122.5, 93.4 (d, J = 179.5
Hz), 52.5 (d, J = 18.1 Hz), 31.3 (d, J = 17.9 Hz), 30.9 (d, J = 5.4 Hz),
24.0, 23.4 (d, J = 10.3 Hz); 19F NMR (282 MHz, CDCl3) δ −178.5 (d,
J = 50.4 Hz); HRMS (ESI+) calculated for C12H16FN2O ([M + H]+),
223.1247; found, 223.1250.
N-(trans-2-Fluorocyclohexyl)thiazole-4-carboxamide (2i).
Chromatographed 5−40% acetone-hexanes; white solid (175 mg,
0.77 mmol, 77% yield; 0.75 mmol scale: 131 mg, 0.57 mmol, 77%
yield). FTIR (thin film, cm−1) 3333, 3116, 2940, 2863, 1638, 1545,
1490, 1027; 1H NMR (500 MHz, CDCl3) δ 8.75 (d, J = 2.1 Hz, 1H),
8.18 (d, J = 2.1 Hz, 1H), 7.40 (br s, 1H), 4.40 (dddd, J = 50.1, 9.7, 9.7,
4.5 Hz, 1H), 4.19−4.08 (m, 1H), 2.25−2.11 (m, 2H), 1.86−1.79 (m,
1H), 1.75−1.60 (m, 2H), 1.48−1.28 (m, 3H); 13C NMR (125 MHz,
CDCl3) δ 160.8, 152.7, 151.2, 123.5, 93.4 (d, J = 179.6 Hz), 52.5 (d, J
= 19.4 Hz), 31.3 (d, J = 18.2 Hz), 31.0 (d, J = 4.8 Hz), 24.4, 23.4 (d, J
= 10.2 Hz); 19F NMR (282 MHz, CDCl3) δ −178.5 (d, J = 44.1 Hz);
trans-Benzyl 3-((tert-Butoxycarbonyl)amino)-4-fluoropyrro-
lidine-1-carboxylate (10): Clear oil (281 mg, 0.83 mmol, 83%
yield; 274 mg, 0.81 mmol, 81% yield); FTIR (thin film, cm−1) 3310,
1
2977, 1682, 1524, 1420, 1357, 1166, 1111, 768; H NMR (500 MHz,
CDCl3, mixture of rotamers) δ 7.40−7.30 (m, 5H), 5.14 (s, 2H), 5.05
(dd, J = 50.1, 13.4 Hz, 1H), 4.60−4.50 (m, 1H), 4.31−4.16 (m, 1H),
3.78−3.58 (m, 3H), 3.50 (d, J = 12.1 Hz, 0.5H), 3.44 (d, J = 11.8 Hz,
0.5H), 1.44 (s, 9H); 13C NMR (125 MHz, CDCl3, mixture of
4181
dx.doi.org/10.1021/jo300433a | J. Org. Chem. 2012, 77, 4177−4183

The Journal of Organic Chemistry
Note
rotamers; rotameric peaks indicated by *) δ 154.92, 154.89, 136.4,
128.7 (2C), 128.3 (2C), 128.2, 94.0 (d, J = 182.0 Hz), 93.1* (d, J =
181.6 Hz), 80.7, 67.4, 54.8 (d, J = 28.2 Hz), 54.0* (d, J = 27.0 Hz),
50.4 (d, J = 23.5 Hz), 50.1* (d, J = 23.5 Hz), 49.7, 49.6*, 28.4 (3C);
19F NMR (282 MHz, MeOD) δ −181.5 (ddddd, J = 90.4, 49.8, 34.5,
ASSOCIATED CONTENT
■
S
* Supporting Information
1H and 13C NMR spectra, chiral GC traces, and crystallographic
data. This material is available free of charge via the Internet at
http://pubs.acs.org.
28.9, 11.4); HRMS (ESI+) calculated for C17H23FN2NaO4 ([M +
Na]+), 361.1534; found, 361.1544.
AUTHOR INFORMATION
Corresponding Author
*E-mail: agdoyle@princeton.edu.
Notes
■
(2R,3S)-Methyl 2-((tert-Butoxycarbonyl)amino)-3-fluorobu-
tanoate (12). Extracted with Et2O; chromatographed 1−15%
acetone-hexanes; pale yellow oil (192 mg, 0.82 mmol, 82% yield,
10:1 dr; after 48 h: 141 mg, 0.60 mmol, 60% yield, 6:1 dr). FTIR (thin
film, cm−1) 3367, 2984, 2927, 1745, 1718, 1512, 1368, 1166; 1H NMR
(500 MHz, CDCl3) δ 5.38 (d, J = 7.4 Hz, 1H), 4.86 (dm, JHF = 46.9
Hz, 1H), 4.46 (dd, J = 22.7, 6.6 Hz, 1H), 3.80 (s, 3H), 1.47−1.39 (s,
9H + m, 3H); 13C NMR (125 MHz, CDCl3) δ 169.6 (d, J = 5.0 Hz),
155.2, 90.7 (d, J = 175.5 Hz), 80.6, 57.7 (d, J = 22.0 Hz), 52.7, 28.4
(3C), 17.5 (d, J = 22.3 Hz); 19F NMR (282 MHz, CDCl3) δ major:
−184.2 (ddq, J = 47.4, 23.7, 23.7 Hz); minor: −185.8 (m); HRMS
(ESI+) calculated for C10H18FNNaO4 ([M + Na]+), 258.1112; found,
258.1114; [α]2D1 = +15.1 (CHCl3, c = 1.39, 98% ee); GC (β-TBDAc, 1
mL/min, 100 °C, 20 min, 10 °C/min, 130 °C, 15 min): tR(minor) =
31.2 min, tR(major) = 33.0 min. The 1H NMR data for both
diastereomers have been reported.36
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank Scott Semproni for the X-ray crystallographic
structure determination of 16 and Lotus Separations for
purification of 8. Financial support was provided by Princeton
University, the NSF (CAREER-1148750), the donors of the
ACS Petroleum Research Fund, the ACS Division of Organic
Chemistry (fellowship to J.A.K. sponsored by Pfizer), and the
Princeton Environmental Institute’s Edward Hayes, Sr. ’18 fund
(undergraduate research fellowship to D.E.S.). This material is
based upon work supported by the National Science
Foundation Graduate Research Fellowship under Grant No.
DGE-0646086 (J.A.K.).
(3S,4S)-Benzyl 3-((tert-Butoxycarbonyl)amino)-4-fluoropi-
peridine-1-carboxylate (14): Clear viscous oil (258 mg, 0.73
mmol, 73% yield, 11:1 rr; on 0.75 mmol scale: 209 mg, 0.59 mmol,
79% yield, 11:1 rr); FTIR (thin film, cm−1) 3330, 2977, 1683, 1523,
1
REFERENCES
1429, 1365, 1229, 1160, 1017, 735; H NMR (500 MHz, MeOD) δ
■
7.44−7.28 (m, 5H), 5.14 (s, 2H), 4.49 (dd, J = 48.8, 3.7 Hz, 1H),
4.03−3.77 (m, 2H), 3.69−3.57 (m, 1H), 3.27−2.97 (m, 2H), 2.18−
2.02 (m, 1H), 1.77−1.63 (m, 1H), 1.46 (s, 9H); 13C NMR (125 MHz,
MeOD) δ 157.8, 156.8, 138.0, 129.6 (2C), 129.2, 129.0, 128.8, 91.2 (d,
J = 180.0 Hz), 80.5, 68.5, 52.0 (d, J = 21.1 Hz), 46.5 (d, J = 4.4 Hz),
41.7, 30.6 (d, J = 43.3 Hz), 28.7 (3C); 19F NMR (282 MHz, MeOD) δ
major: −184.9 (m); minor: −190.5 (m); HRMS (ESI+) calculated for
C18H25FN2NaO4 ([M + Na]+), 375.1696; found, 375.1691.
(1) Bergstrom, C. G.; Nicholson, R. T.; Dodson, R. M. J. Org. Chem.
1963, 28, 2633−2640.
(2) For a review, see: Yoneda, N. Tetrahedron 1991, 47, 5329−5365.
(3) Olah, G. A.; Welch, J. T.; Vankar, Y. D.; Nojima, M.; Kerekes, I.;
Olah, J. A. J. Org. Chem. 1979, 44, 3872−3881 and references therein.
(4) Haufe, G. J. Prakt. Chem. 1996, 338, 99−113.
(5) Nelson, T. D.; Crouch, R. D. Synthesis 1996, 1031−1069.
(6) Kalow, J. A.; Doyle, A. G. J. Am. Chem. Soc. 2010, 132, 3268−
3269.
(7) Kalow, J. A.; Doyle, A. G. J. Am. Chem. Soc. 2011, 133, 16001−
16012.
(8) For a review, see: Purser, S.; Moore, P. R.; Swallow, S.;
Gouverneur, V. Chem. Soc. Rev. 2008, 37, 320−330.
(9) For two examples directly relevant to this work, see: (a) Coburn,
C. A.; Egbertson, M. S.; Graham, S. L.; McGaughey, G. B.; Stauffer, S.
R.; Yang, W.; Lu, W.; Fahr, B. PCT International Patent Application
US2006/027544, July 14, 2006. (b) Burger, M.; Lan, J.; Lindvall, M.;
Nishigughi, G.; Tetalman, M. PCT International Patent Application
EP2009/052506, March 3, 2009.
(1S,2S)-2-Fluoro-N-((S)-1-phenylethyl)cyclohexanamine
((1S,2S,1′S)-16). Extracted with DCM; chromatographed 5−40%
EtOAc-hexanes; clear oil (140 mg, 0.63 mmol, 63% yield, >30:1 dr;
126 mg, 0.57 mmol, 57% yield, >30:1 dr). FTIR (thin film, cm−1)
1
3026, 2936, 2863, 1493, 1450, 1130, 1025, 761; H NMR (500 MHz,
CDCl3) δ 7.36−7.28 (m, 4H), 7.25−7.19 (m, 1H), 4.29 (dddd, J =
48.9, 10.5, 10.4, 4.7 Hz, 1H), 3.98 (q, J = 6.6 Hz, 1H), 2.57 (qd, J =
9.9, 4.3 Hz, 1H), 2.10−1.99 (m, 1H), 1.72−1.38 (m, 5H), 1.34 (d, J =
6.6 Hz, 3H), 1.28−0.95 (m, 3H); 13C NMR (125 MHz, CDCl3) δ
147.0, 128.5 (2C), 126.8, 126.6 (2C), 97.7 (d, J = 174.2 Hz), 59.3 (d, J
= 16.3 Hz), 56.8 (d, J = 1.8 Hz), 31.7 (d, J = 7.5 Hz), 31.3 (d, J = 18.0
Hz), 24.9, 24.1 (d, J = 1.6 Hz), 23.7 (d, J = 11.1 Hz); 19F NMR (282
MHz, CDCl3) δ major: −177.2 (d, J = 52.0 Hz); minor: −180.0 (d, J =
51.0 Hz); HRMS (ESI+) calculated for C14H21FN ([M + H]+),
222.1653; found, 222.1656.
(10) (a) O’Hagan, D. Chem. Soc. Rev 2008, 37, 308−319. For
examples, see: (b) Morgenthaler, M.; Schweizer, E.; Hoffmann-Roder,
A.; Benini, F.; Martin, R. E.; Jaeschke, G.; Wagner, B.; Fischer, H.;
Bendels, S.; Zimmerli, D.; Schneider, J.; Diederich, F.; Kansy, M.;
Muller, K. ChemMedChem 2007, 2, 1100−1115.
̈
̈
(11) For examples, see: (a) Andrews, P. C.; Bhaskar, V.; Bromfield,
K. M.; Dodd, A. M.; Duggan, P. J.; Duggan, S. A. M.; McCarthy, T. D.
Synlett 2004, 791−794. (b) Malamakal, R. M.; Hess, W. R.; Davis, T.
A. Org. Lett. 2010, 12, 2186−2189. (c) Appayee, C.; Brenner-Moyer,
S. E. Org. Lett. 2010, 12, 3356−3359. (d) Schulte, M. L.; Lindsley, C.
W. Org. Lett. 2011, 13, 5684−5687.
(12) (a) Hu, X. E. Tetrahedron Lett. 2002, 43, 5315−5318. (b) Fan,
R.-H.; Zhou, Y.-G.; Zhang, W.-X.; Hou, X.-L.; Dai, L.-X. J. Org. Chem.
2004, 69, 335−338. (c) Ding, C.-H.; Dai, L.-X.; Hou, X.-L. Synlett
2004, 2218−2220. (d) van Oosten, E. M.; Gerken, M.; Hazendonk, P.;
Shank, R.; Houle, S.; Wilson, A. A.; Vasdev, N. Tetrahedron Lett. 2011,
52, 4114−4116.
tert-Butyl ((1S,2S)-2-Fluorocyclohexyl)carbamate ((S,S)-2a).
A round-bottom flask capped with a rubber septum containing
(S,S,1′S)-16 (111 mg, 0.5 mmol) and Boc2O (0.33 g, 1.5 mmol) was
evacuated and backfilled with N2 (3×). Pd(OH)2/C (20 wt %, 26 mg)
was charged, and the flask was again evacuated and backfilled with N2
(3×). EtOH (6.25 mL) was charged via syringe, and the flask was
evacuated and backfilled with H2 (3×). The reaction was stirred under
a balloon of H2 for 8 h, until TLC indicated complete consumption of
the starting material. Upon completion, the reaction was filtered
through Celite, rinsing with EtOAc, and concentrated in vacuo. The
crude material was purified by column chromatography (5−40% Et2O-
hexanes) to obtain the title product as a white solid (107 mg, 0.49
mmol, 98% yield). Spectral data were consistent with those of the
racemate; [α]2D2 = +27.5 (CHCl3, c = 1.01, 99% ee). GC (Cyclodex-B,
1 mL/min, 130 °C isotherm): tR(minor) = 34.9, tR(major) = 35.5 min.
(13) Wade, T. N. J. Org. Chem. 1980, 45, 5328−5333 and references
therein.
(14) Alvernhe, G. M.; Ennakoua, C. M.; Lacombe, S. M.; Laurent, A.
J. J. Org. Chem. 1981, 46, 4938−4948 and references therein.
4182
dx.doi.org/10.1021/jo300433a | J. Org. Chem. 2012, 77, 4177−4183

The Journal of Organic Chemistry
Note
(15) The hydrofluorinations of aziridines 1b and 1c displayed
comparable efficiency in glass vials under otherwise identical
conditions: 2b (93% yield), 2c (84% yield).
(16) Sasaki, M.; Dailili, S.; Yudin, A. K. J. Org. Chem. 2003, 68,
2045−2047.
(17) Arai, H.; Sugaya, N.; Sasaki, N.; Makino, K.; Lectard, S.;
Hamada, Y. Tetrahedron Lett. 2009, 50, 3329−3332.
(18) Schramm, H.; Pavlova, M.; Hoenke, C.; Christoffers, J. Synthesis
2009, 1659−1662.
(19) (a) le Huerou, Y.; Blake, J. F.; Gunwardana, I. W.; Mohr, P.;
Wallace, E. M.; Wang, B.; Chicarelli, M.; Lyon, M. PCT International
Patent Application US2009/043691, May 13, 2009. (b) Ninkovic, S.;
Braganza, J. F.; Collins, M. R.; Kath, J. C.; Li, H.; Richter, D. T. PCT
International Patent Application IB2009/053389, August 4, 2009.
(20) For a recent review, see: Lectard, S.; Hamashima, Y.; Sodeoka,
M. Adv. Synth. Catal. 2010, 352, 2708−2732.
(21) For representative examples with O, S, Se, and N nucleophiles,
see: (a) Chandrasekhar, M.; Sekar, G.; Singh, V. K. Tetrahedron Lett.
2000, 41, 10079−10083. (b) Ekegren, J. K.; Roth, P.; Kallstrom, K.;
̈
̈
Tarnai, T.; Andersson, P. G. Org. Biomol. Chem. 2003, 1, 358−366.
(c) Kumar, M.; Gandhi, S.; Singh Kalra, S.; Singh, V. K. Synth.
Commun. 2008, 38, 1527−1532. (d) Per
́
ez-Bautista, J. A.; Sosa-
Rivadeneyra, M.; Quintero, L.; Hopfl, H.; Tejeda-Dominguez, F. A.;
̈
Sartillo-Piscil, F. Tetrahedron Lett. 2009, 50, 5572−5574.
(22) Et3N-3HF (20 equiv), DCM, rt, 24 h (ref 14): 27% yield, 3.0:1
dr. KF·2H2O (2 equiv), n-Bu4NHSO4 (1 equiv), MeCN, 45 °C, 24 h
(ref 12b): <5% yield, dr not determined.
(23) The relative stereochemistry of the diastereomers was assigned
by X-ray crystallography of the minor diastereomer (1R,2R,1′S)-
16·HCl.
(24) Watson, I. D. G.; Afagh, N.; Yudin, A. K. Org. Synth. 2010, 87,
161−169.
(25) Sasaki, T.; Kanematsu, K.; Yukimoto, Y. J. Org. Chem. 1972, 37,
890−894.
(26) Tanner, D.; Birgersson, C.; Gogoll, A. Tetrahedron 1994, 50,
9797−9824.
(27) Rowland, E. B.; Rowland, G. B.; Rivera-Otero, E.; Antilla, J. C. J.
Am. Chem. Soc. 2007, 129, 12084−12085.
(28) Koppel, H. C.; Springer, R. H.; Robins, R. K.; Schneider, F. H.;
Cheng, C. C. J. Org. Chem. 1962, 27, 2173−2177.
(29) da Zhang, Z.; Scheffold, R. Helv. Chim. Acta 1993, 76, 2602−
2615.
(30) Ekegren, J. K.; Roth, P.; Kallstrom, K.; Tarnal, T.; Andersson, P.
̈
̈
G. Org. Biomol. Chem. 2003, 1, 358−366.
(31) Watson, I. D. G.; Yudin, A. K. J. Org. Chem. 2003, 68, 5160−
5167.
(32) Hayashi, M.; Ono, K.; Hoshimi, H.; Oguni, N. Tetrahedron
1996, 52, 7817−7832.
(33) Coburn, C. A.; Egbertson, M. S.; Graham, S. L.; McGaughey, G.
B.; Stauffer, S. R.; Yang, W.; Lu, W.; Fahr, B. Patent WO 2007/11810
A1, January 25, 2007.
(34) The procedure in ref 31 was used. Spectral data were consistent
with literature values: Shaw, K. J.; Luly, J. R.; Rapoport, H. J. Org.
Chem. 1985, 50, 4515−4523.
(35) Anaya de Parrodi, C.; Moreno, G. E.; Quintero, L.; Juaristi, E.
Tetrahedron: Asymmetry 1998, 9, 2093−2099.
(36) Vidal-Cros, A.; Bory, S.; Gaudry, M.; Marquet, A. Tetrahedron
Lett. 1989, 30, 1799−1802.
4183
dx.doi.org/10.1021/jo300433a | J. Org. Chem. 2012, 77, 4177−4183