The role of organic fluorine in directing alkylation reactions via lithium chelation

Article abstract of DOI:10.1016/j.jfluchem.2004.09.015

The fluorine of a fluoromethyl group displays a measurable chelation effect to lithium during α-methylation of an ester with lithium diisopropylamide (LDA) and methyl iodide. A series of esters is compared with F, H and O, and the resultant diastereoselectivity is consistent with the intermediate capacity of F to chelate lithium relative to H and O. In a second system which involved comparing a tertiary organic fluorine with hydrogen, no such effect is apparent, most probably due to adverse steric effects. The absolute and relative stereochemistry of the predominant diastereoisomers are confirmed by X-ray crystallography of suitable crystalline derivatives in each case. It is concluded that there is a potential role for organic-bound fluorine to become involved in lithium chelation in well-designed enolate alkylation systems. The diastereoselectivity of alkylation is explored comparing the coordination ability of H, F and OR substituents in the above model.

Full text of DOI:10.1016/j.jfluchem.2004.09.015

Journal of Fluorine Chemistry 125 (2004) 1779–1790
www.elsevier.com/locate/fluor
The role of organic fluorine in directing alkylation
reactions via lithium chelation
a
Kenny Tenza , Julian S. Northen , David O’Hagan , Alexandra M.Z. Slawin
b
a,
a
*
aSchool of Chemistry, University of St Andrews, North Haugh, St Andrews KY16 9ST, UK
bOnyx Scientific Ltd., Units 97/98 Silverbriar, Sunderland Enterprise Park East, Sunderland SR5 2TQ, UK
Available online 18 November 2004
Abstract
The fluorine of a fluoromethyl group displays a measurable chelation effect to lithium during a-methylation of an ester with lithium
diisopropylamide (LDA) and methyl iodide. A series of esters is compared with F, H and O, and the resultant diastereoselectivity is consistent
with the intermediate capacity of F to chelate lithium relative to H and O. In a second system which involved comparing a tertiary organic
fluorine with hydrogen, no such effect is apparent, most probably due to adverse steric effects. The absolute and relative stereochemistry of the
predominant diastereoisomers are confirmed by X-ray crystallography of suitable crystalline derivatives in each case. It is concluded that there
is a potential role for organic-bound fluorine to become involved in lithium chelation in well-designed enolate alkylation systems.
# 2004 Elsevier B.V. All rights reserved.
Keywords: Lithium enolates; Organic fluorine; Diastereoselectivity
1. Introduction
the fluorine of a fluoromethyl group can induce a
diastereoselectivity of 82–90% de (diastereomeric excess)
in the products 5–7 after the methylation reactions illustrated
in Scheme 1. The de’s were higher for other alkylations
involving benzyl bromide and allyl iodide. In the case of 1, it
is only the replacement of F for H which can account for this
diastereoselectivity, and it was argued that fluorine is
chelating lithium in the bicyclo[3.3.0] intermediate enolate 4
as shown in Scheme 1. The stereogenic centre in these
substrates is a tertiary ether and the steric influence of this
tertiary centre is clearly significant and contributes in part to
the efficiency of chirality transfer in these reactions.
The ability of carbon-bound oxygen to chelate to lithium
is a central tenet in organic chemistry and the strategy has
been used widely to design pre-organisation into chemical
reactions [1–6]. Of course carbon-bound hydrogen is not an
obvious candidate for coordination to lithium and other
metal cations and is not a useful atom for designing pre-
organisation into a reaction system. In this paper, we explore
the ability of organic-bound fluorine to influence the
stereoselectivity of lithium enolate reactions. In this regard,
an organic fluorine is an intermediate between oxygen and
hydrogen, and there have been some recent reports that it
performs very well as a lithium chelator in asymmetric
alkylation reactions [7–11]. Of course organic bound
fluorine is not an immediately obvious candidate for lithium
chelation particularly as it is a moderate to poor hydrogen
bonding acceptor [12,13]. Probably the most impressive
results have been reported by Yamazaki et al. [14] who have
demonstrated convincingly in an experimental system that
Prompted by these reports, and a by general focus on
evaluating the experimental influence of fluorine in organic
chemistry, it appeared appropriate to examine a series of
enolates whereby the substrate varies only at a remote site. It
was a particular focus of this study to examine the relative
coordination of H, F and O in a given series. Two such
studies are reported. In the first case, the substrates varied by
changing the CH2-X group attached to a secondary ether and
it was envisaged that the enolate intermediates in this
reaction may find stabilisation by coordination to the X
group. In a second study, we report results which have
* Corresponding author. Tel.: +44 1334 467176; fax: +44 1334 463808.
E-mail address: do1@st-and.ac.uk (D. O’Hagan).
0022-1139/$ – see front matter # 2004 Elsevier B.V. All rights reserved.
doi:10.1016/j.jfluchem.2004.09.015

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K. Tenza et al. / Journal of Fluorine Chemistry 125 (2004) 1779–1790
Scheme 1.
study. In order to prepare the monofluorinated substrate 12,
benzyl alcohol 20 was prepared from benzoyl chloride 18 by
treatment with diazomethane and then HF–pyridine [17].
Sodium borohydride reduction of the resultant a-fluoroa-
cetophenone 19 gave alcohol 20 as illustrated in Scheme 3.
Compounds 9–13 were then subjected to the methylation
reactions. They are all a-substituted benzylic ethers,
however the benzylic a-ether substituents differ in size
and coordinating ability.
Fig. 1. Substrate structures.
explored the ability of organic-bound fluorine, relative to
hydrogen, to influence the diastereoselectivity in a much
more sterically congested substrate system.
Benzyl ether 8 (where X = H) was used as the reference
substrate in the methylation reaction as there was no
expectation that hydrogen would chelate the lithium enolate
during alkylation. Consistent with this, the resultant product
was found to be a 1:1 mixture of diastereoisomers. On the
other hand, it was anticipated that the good donor properties
of oxygen would facilitate oxygen to lithium chelation and
influence the diastereoselectivity. In the event, this proved to
be the case and interestingly the isopropyl ether 10 displayed
the highest diastereoselectivity. The smaller methyl and
larger t-butyl ether substrates 9 and 11 were less good and it
would appear that the optimal diastereoselectivity resulted
due to a balance between the steric influence and coordi-
nation ability of the different ethers.
2. Results and discussion
Benzyl ethers 8–13 (Fig. 1) were selected for this study as
they represented substrates which could be readily alkylated
(methylated) after treatment with LDA, and as a series they
allowed the exploration of the relative abilities of oxygen,
hydrogen and fluorine (at the X-site) to coordinate to lithium
in the intermediate enolate. Also these compounds were
accessible by straightforward synthesis protocols (see
Schemes 2,3 and 4).
The diastereomeric excesses of the mono- and tri-fluoro
benzyl ethers 12 and 13 [18] were studied and the results
are shown in Table 1. In both cases, the diastereoselectivity
was the same at 33% de. A direct comparison of substrates
12 and 8 indicates the influence of the F over H and clearly
the incorporation of a single fluorine atom has had a
significant and beneficial effect, but not as significant as
the oxygen series. This is exactly in keeping with our
preconceived understanding of the relative donor abilities of
oxygen, fluorine and hydrogen. The result for substrate 13
indicated no apparent benefit in increasing the number
of fluorine atoms at the potential coordination site (see
Table 1).
2.1. Synthesis of benzyl ether substrates 8–13
The substrates for the study were prepared by a
straightforward Williamson’s ether protocol [15] between
the relevant benzyl alcohol and ethyl iodoacetate. For
substrates 9–11 the relevant benzyl alcohols 15–17 were
prepared by alkoxide ring opening of styrene oxide [16].
These reactions gave a mixture of regioisomers a and b,
as shown in Scheme 2. Regioisomer b was identified as a
major product in all of the cases studied. The regioisomers
were readily separated by chromatography and the major
regioisomers 15–17 were isolated and used further in this
In view of the high diastereoselectivity observed in the
methylation of isopropyl ether 10, an assessment of the
Scheme 3. (a) (i) CH2N2, (CH3CH2)2O; (ii) HF Py (70/30), 39%; (b)
NaBH4, CH3OH, 99%.
Scheme 2.

K. Tenza et al. / Journal of Fluorine Chemistry 125 (2004) 1779–1790
1781
Table 1
which gave product 43 with a diasteroisomeric ratio of 2: 1.
Thus the fluorinated substrate performed less well.
Diastereoselectivities of methylation reactions with substrates 8–13
Substrate Product R
Diastereomeric ratio (dr): Diastereomeric
The benzyl group of 36 was removed to give 37 and the
hydrochloride 38 was generated after treatment with
hydrochloric acid. Recrystallisation of hydrochloride 38
amplified the predominant diastereoisomer in that series and
X-ray diffraction analysis of a suitable crystal of the major
stereoisomer revealed the absolute and relative configuration
of 38 as shown in Scheme 6 and Fig. 3.
(a) NMR/(b) GC–MS
excess (%de)
8
CH3 (21)
1:1 (b)
1:5 (b)
–
9
CH2OMe (22)
67
88
44
33
33
10
11
12
13
CH2O–i-Pr (23) 1:15 (b)
CH2O–t-Bu (24) 1:2.6 (a)
CH2F (25)
CF3 (26)
1:2 (a)
1:2 (a)
All de values of the methylation products 21–26 were determined by 1H
NMR/GC–MS analyses of crude reaction products.
It was anticipated that the intermediate enolate 44 derived
from 43 may find additional stabilisation by lithium
chelation to fluorine and that this may increase the
diastereoselectivity of the methylation reaction. In the event
the fluorinated analogue showed a poorer diastereoselec-
tivity when compared with 34, the non-fluorinated analogue,
although we do not know if the predominant diasteroisomer
has the same relative configuration as that established for 36.
preferred relative stereochemistry of the methylation
reaction was explored by using an enantiomerically pure
substrate of known absolute configuration. Sequential
treatment of the styrene oxide (R)-14 with sodium
isopropoxide and ethyl iodoacetate furnished (R)-10 as
illustrated in Scheme 5. The methylated ester product (R,R)-
23 was then reduced to alcohol (R,R)-27 by treatment with
lithium aluminium hydride, followed by a Jones oxidation
to access the carboxylic acid (R,R)-28. Preparation and
recrystallisation of the major diastereoisomer of the
morpholinium salt (R,R)-29 of carboxylic acid (R,R)-28
afforded a suitable crystal for X-ray structure analysis and
this revealed the (R,R) absolute configuration of the product.
The resultant structure is shown in Fig. 2.
3. Conclusions
In summary, this study has shown that there is a clear
fluorine effect in an alkylation model involving a
fluoromethyl group as a component of a lithium enolate
derived from a secondary ether functionality. The effect of
the fluorine on the resultant diastereoselectivity of a
methylation reaction is modest for 12 and 13 relative to
the oxygen substituents in 9 and 10. A second study with
substrates 34 and 35 compared H with F at a tertiary centre
and indicated a small but measurable difference in the
performance of the chiral auxiliary. It is concluded that the
fluorine atom can influence the efficacy of a chiral auxiliary
most probably due to a coordination ability to lithium.
2.2. A sterically more hindered system
In order to try to extend the lithium enolate alkylation
strategy, a sterically more complex system was investigated.
Thus the diastereoselectivity of the methylation of the amine
esters 34 and 43, which we envisaged may proceed via
enolate intermediates 35 and 44, respectively, as shown in
Schemes 6 and 7, was explored.
The aminoester substrates 34 and 43 were prepared from
the commercially available amines 30 and 39, respectively.
The routes to the hydro and fluoro analogues 34 and 43
follow each other closely and are outlined in Schemes 6 and
7, respectively. In the event, it was apparent from product
analysis after the methylation reactions that the non-
fluorinated aminoester 34 generated product 36 with a
higher de (60%, ratio 4:1) than the fluorinated amine 41,
4. Experimental
Air- and moisture-sensitive reactions were carried out
under a positive pressure of nitrogen in oven-dried (200 8C)
glassware. Room temperature (RT) refers to 20–25 8C.
Evaporations were carried under reduced pressure on a
Bu¨chi rotary evaporator. All reagents were of synthetic
grade and were used without further purification. Solvents
Scheme 4. (a) CH3I, LDA, THF.

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K. Tenza et al. / Journal of Fluorine Chemistry 125 (2004) 1779–1790
Scheme 5. Reagents: (a) (CH3)2CHOH, NaH, 92%; (b) ICH2COEt, THF, 73%; (c) MeI, LDA, THF, 87%; (d) LiAlH4, THF, 100%; (e) Jones’s reagent, 96%;
(f) Morpholine, hexane, 100%.
and reagents were dried according to standard methods prior
to use.
and 282.4 for 19F, and Varian Unity Plus 300 MHz operating
1
at 300.00 MHz for H, 75.43 MHz for 13C. All chemical
Optical rotations were measured using Optical Polari-
meter Ltd. A-1000 as solutions in dichloromethane
(CH2Cl2). Specific rotations are given in units of 10ꢀ18 gꢀ1
dmꢀ1. High-resolution mass spectra were recorded on VG
AUTOSPEC and VG PLATFORM spectrometers.
Infrared spectra were recorded with Perkin Elmer
2000 FTIR instrument as a thin layer between NaCl disks.
Solid materials were prepared with KBr pellets. Values
were rounded to 5 cmꢀ1. Melting points were measured
on a Gallenkamp Griffin MPA350.BM2.5 melting point
apparatus.
shifts are reported as d values down-fielded from (CH)4Si
using CDCl3 as internal standard (dH 7.24 or dC 77.00 ppm,
for 1H and 13C, respectively) and CFCl3 (0.00 ppm) for 19F.
All coupling constants (J) are given in hertz (Hz). Spectral
coupling patterns are designated as follows: s: singlet; d:
doublet; t: triplet; q: quartet; m: multiplet; br; broad signal.
1
The assignments of the signals in the H NMR spectra are
based on the first-order analysis of the spin systems and
1
when required were confirmed by H{1H} decoupling and
two-dimensional (2D) (1H, 1H) homonuclear chemical shift
correlation (COSY) experiments. The 13C chemical shifts
were obtained from proton-decoupled spectra. Standard
Bruker pulse sequence programs were used in these
experiments.
Nuclear magnetic resonance (NMR) spectra were
measured for CDCl3 solutions on a Bruker Av-300.00
(7.0 T) operating at 300.00 MHz for 1H, 75.45 MHz for 13
C
Reaction progress was monitored on thin-layer chro-
matography (TLC) using glass plates coated with silica
gel 60 F254 (Merck). Plates were visualised under UV light
(254 and 366 nm). Column chromatography was per-
formed on Merck silica gel 60 (60–200 mm, 70–230
mesh).
Standard work-up procedure: The reaction mixture was
quenched with water and the aqueous layer extracted into
diethyl ether (3ꢁ). The organics were dried over MgSO4,
filtered and concentrated under reduced pressure. * denotes
minor diastereoisomer whenever identifiable.
4.1. Procedures
General procedure for the preparation of alcohols 8–10
from styrene oxide followed a previously described method
[16]. Yields and analytical data for the resultant products
were as follows.
Fig. 2. ORTEP structure of (R,R)-29 used to assess the predominant relative
configuration for methylation of substrate 10.

K. Tenza et al. / Journal of Fluorine Chemistry 125 (2004) 1779–1790
1783
Scheme 6. Reagents: (a) PhCHO, NaCNBH3, CH3OHꢂHCl, 82%; (b) ClCOCO2C2H3, Et3N, CH2Cl2, 99%; (c) (i) NaOH, ethanol, D; (ii). BH3ꢂTHF, D, AcOH,
60%; (d) CH2N2, Et2O, 100%; (e) LDA, CH3I, THF, 68%; (f) Pd(OH)2/C (20%)/CH3OH, 100%; (g) HCl (anhydrous).
4.1.1. 2-Methoxy-1-phenylethanol (15)
4.1.3. 2-tert-Butoxy-1-phenylethanol (17) [19]
The product (1.10 g, 68%) was recovered as a colourless
The product (1.7 g, 67%) was recovered as a colourless
oil. IR (neat); n 3425, 2893, 1453, 1195, 1120; 1H NMR: d
3.22 (1H, br s, OH), 3.23 (3H, s, OCH3), 3.35 (1H, dd,
J = 8.8, 9.9, CH2OCH3), 3.45 (1H, dd, J = 3.3, 9.9,
CH2OCH3), 4.79 (1H, dd, J = 3.3, 8.8) and 7.19–7.28
(5H, m, Ph); 13C NMR: d 59.4 (OCH3), 73.0 (PhCH), 78.6
(CH2OCH3), 126.5 (C-2 of Ph), 128.2 (C-4 of Ph), 128.9
(C-3 of Ph) and 140.7 (C-1 of Ph); MS (CI) m/z (rel. int.):
152 [M]+ (7), 135 [M ꢀ H2O]+ (100), 121 [M ꢀ OCH3]+
(7), 107 [M ꢀ CH2OCH3]+ (8).
1
oil, IR (neat); n 3452, 2975, 1453, 1364, 1199; H NMR: d
1.13 [9H, s, OC(CH3)3], 3.02 (1H, br s, OH), 3.24 [1H, dd,
J = 9.0, 9.2, CH2OC(CH3)3], 3.43 [1H, dd, J = 3.1, 9.0,
CH2OC(CH3)3], 4.71 (1H, dd, J = 3.1, 9.2, PhCH), 7.19–
7.33 (5H, m, Ph); 13C NMR: d 27.5 [OC(CH3)3], 67.8
[CH2OC(CH3)3], 73.1 (PhCH), 73.5 [OC(CH3)3], 126.1
(C-3 of Ph), 127.6 (C-4 of Ph), 128.2 (C-2 of Ph), 140.5 (C-1
of Ph), MS (EI) m/z (rel. int.): 216.8 [M + Na]+ (100).
4.2. General procedure A: preparation of benzyl
alcohols (8–11)
4.1.2. 2-Isopropoxy-1-phenylethanol (16)
The product (1.35 g, 90%) was recovered as a colourless
1
oil. IR (neat); n 3459, 2973, 1755, 1453, 1199, 1129; H
A stirred solution of 1-phenylethanol 15–17 (810 mg,
5.32 mmol) in THF (20 ml) was treated with sodium hydride
(255 mg, 6.4 mmol). After 15 min, ethyl iodoacetate was
added and the reaction stirred for a further 5 h at rt. The
products were isolated following the standard work-up
procedure. The products were recovered after silica gel
chromatography.
NMR: d 1.21 [3H, d, J = 6.0, OCH(CH3)2], 1.22 [3H, d,
J = 6.0, OCH(CH3)2], 2.99 (1H, br s, OH), 3.39 [1H, m,
OCH(CH3)2], 3.62 [1H, dd, J = 3.1, 9.6, CH2OCH(CH3)2],
3.69 [1H, dd, J = 6.1, 9.6, CH2OCH(CH3)2], 4.86 (1H, dd,
J = 3.1, 9.6, PhCH) and 7.27–7.42 (5H, m, Ph); 13C NMR: d
21.9 [OCH(CH3)2], 72.1 [OCH(CH3)2], 73.7 (PhCH), 73.8
[CH2OCH(CH3)2], 126.0 (C-2 of Ph), 127.6 (C-4 of Ph),
128.2 (C-3 of Ph) and 140.3 (C-1 of Ph); MS (CI) m/z
(rel. int.): 163 [MH ꢀ H2O]+ (100), 121 [MH ꢀ i-PrOH]+
(30).
4.2.1. Ethyl(1-phenylethoxy)acetate (8)
The product was prepared following general procedure A
from 1-phenylethanol (500 mg, 4.09 mmol), sodium hydride
(150 mg, 6.14 mmol) and ethyl iodoacetate (1.14 g,
5.33 mmol) in THF (15 ml) to afford the title compound
as a colourless oil (830 mg, 98%). IR (neat): n 2981, 1754,
1452, 1133, 1119; 1H NMR: d 1.25 (3H, t, J = 7.2,
OCH2CH3), 1.52 (3H, d, J = 6.4, OCHCH3), 3.87 (1H, d,
J = 16.4, OCH2CO), 3.96 (1H, d, J = 16.4, OCH2CO), 4.18
4.1.2.1. (R)-Isopropoxy-1-phenylethanol (R)-16. The pro-
duct (1.20 g, 92%) was recovered as a colourless oil,
[a]D20 = ꢀ71.1 (ca. 0.65, CH2Cl2), with identical spectro-
scopic data to 16.

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K. Tenza et al. / Journal of Fluorine Chemistry 125 (2004) 1779–1790
Scheme 7. Reagents: (a) and (b) as in Scheme 5 above; (c) LiAlH4/THF, D, 100%; (d) (i) Dess-Martin periodinate, DCM, 100% (crude), (ii) NaOCl2, KH2PO4/
H2O, CH3CH=C(CH3)2, t-BuOH, 30%; (e) CH2N2/Et2O, 100%; (f) CH3I, LDA/THF, 60%.
(2H, q, J = 7.2, OCH2CH3), 4.56 (1H, q, J = 6.4, PhCH) and
7.32–7.35 (5 H, m, Ph); 13C NMR: d 14.0 (OCH2CH3), 23.7
(OCHCH3), 60.6 (OCH2CH3), 65.7 (OCH2CO), 78.4
(PhCH), 126.3 (C-3 of Ph), 127.7 (C-4 of Ph), 128.4 (C-2
of Ph), 142.3 (C-1 of Ph) and 170.4 (CO); MS (EI) m/z (rel.
int.): 230.8 [M + Na]+ (100); HRMS (EI) Calc. for
C12H16O3 + Na: 231.0997, Found 231.1001.
4.02 (1H, d, J = 16.4, OCH2CO), 4.08 (2H, m, OCH2CH3),
4.62 (1H, dd, J = 3.4, 7.9, PhCH) and 7.26–7.28 (5H, m, Ph);
13C NMR: d 14.5 (OCH2CH3), 59.5 (OCH3), 61.1
(OCH2CH3), 66.5 (OCH2CO), 77.5 (CH2OCH3), 81.7
(PhCH), 127.5 (C-2 of Ph), 128.7 (C-4 of Ph), 128.9 (C-3
of Ph), 138.4 (C-1 of Ph) and 170.6 (CO), MS (CI) m/z (rel.
int.): 239 [MH]+ (8), 207 [MH ꢀ HOCH3]+ (20), 193
[MH ꢀ CH3CH3]+ (25), 135 [MH ꢀ HOCH2CO2Et]+ (100);
HRMS (CI) Calcd. for C13H19O4: 239.1295, Found
239.1283.
4.2.2. Ethyl(2-methoxy-1-phenylethoxy)acetate (9)
The product (980 mg, 77%) was recovered as a colourless
1
oil. IR (neat): n 2983, 1754, 1453, 1306, 1202, 1130; H
4.2.3. Ethyl(2-isopropoxy-1-phenylethoxy)acetate (10)
The product (400 mg, 73%) was recovered as a colourless
1
oil. IR (neat): n 2974, 1756, 1453, 1380, 1202, 1130; H
NMR: d 1.16 (3H, dd, J = 7.2, OCH2CH3), 3.33 (3H, s,
OCH3), 3.42 (1H, d, J = 3.4, 10.7, CH2OCH3), 3.65 (1H, dd,
J = 7.9, 10.7, CH2OCH3), 3.89 (1H, d, J = 16.4, OCH2CO),
NMR: d 1.04 [3H, d, J = 6.1, OCH(CH3)2], 1.08 [3H, d,
J = 6.0, OCH(CH3)2], 1.17 (3H, t, J = 7.2, OCH2CH3), 3.47
[1H, dd, J = 4.1, 10.6, CH2OCH(CH3)2], 3.68 [1H, dd,
J = 7.4, 10.6, CH2OCH(CH3)2], 3.92 (1H, d, J = 16.4,
OCH2CO), 4.06 (1H, d, J = 16.4, OCH2CO), 4.10 (2H, q,
J = 7.2, OCH2CH3), 4.54 (1H, dd, J = 4.1, 7.4, PhCH) and
7.19–7.29 (5 H, m, Ph); 13C NMR: d 14.1 (OCH2CH3), 21.9
[OCH(CH3)2], 22.0 [OCH(CH3)2], 60.6 (OCH2CH3), 66.5
(OCH2CO), 72.1 [OCH(CH3)2], 72.7 [CH2OCH(CH3)2],
82.0 (PhCH), 127.1 (C-3 of Ph), 128.0 (C-4 of Ph), 128.3 (C-
2 of Ph), 138.6 (C-1 of Ph) and 170.3 (CO); MS (CI) m/z (rel.
int.): 267 [MH]+ (13), 193 [MH ꢀ CH3CH(CH3)2]+ (22),
163 [MH ꢀ HOCH2CO2Et]+ (100), 121 [MH ꢀ CH3CO2Et
ꢀ iPrOH]+ (45); HRMS (CI) Calc. for C15H23O4: 267.1596,
Found 267.1603.
4.2.3.1. (R)-Ethyl(isopropoxy-1-phenylethoxy)acetate
(R)-10. The product (700 mg, 90%) was recovered as a
20
D
colourless oil ½aŠ = ꢀ48.0 (ca. 0.10, CH2Cl2), with
Fig. 3. ORTEP structure of hydrochloride 38.
identical spectroscopic data to 10.

K. Tenza et al. / Journal of Fluorine Chemistry 125 (2004) 1779–1790
1785
4.2.4. Ethyl(2-tert-butoxy-1-phenylethoxy)acetate (11)
The product (182 mg, 73%) was recovered as a colourless
oil. IR (neat): n 2976, 1732, 1307, 1198, 1133; 1H NMR: d
1.12 [9H, s, OC(CH3)3], 1.24 (3H, t, J = 7.2, OCH2CH3),
3.47 [1H, dd, J = 4.6, 9.9, CH2OC(CH3)3], 3.71 [1H, dd,
J = 6.9, 9.9, CH2OC(CH3)3], 4.05 (1H, d, J = 16.4,
OCH2CO), 4.17 (1H, d, J = 16.4, OCH2CO),4.26 (2H, q,
J = 7.2, OCH2CH3), 4.54 (1H, dd, J = 4.6, 6.9, PhCH),
7.03–7.36 (5H, m, Ph); 13C NMR: d 14.1 (OCH2CH3),
27.3 [OC(CH3)3], 60.5 (OCH2CH3), 66.8 [CH2OC(CH3)3],
67.9 (OCH2CO), 73.1 [OC(CH3)3], 82.3 (PhCH),
127.1 (C-3 of Ph), 128.0 (C-4 of Ph), 128.2 (C-2 of Ph),
139.0 (C-1 of Ph), 170.4 (CO); MS (CI) m/z (rel. int.):
281 [MH]+ (23), 255 [MH ꢀ CH(CH3)3]+ (66), 207
[MH ꢀ HOC(CH3)3]+ (10), 121 [MH ꢀ CH3CO2Et ꢀ
HOC(CH3)3]+ (10); HRMS (CI) Calc. for C16H25O4:
281.1753, Found 281.1755.
3.84 (1H, q, J = 6.9, OCHCH3), 4.13 (2H, q, J = 7.2,
OCH2CH3), 4.48 (1H, dd, J = 5.4, 6.1, PhCH) and 7.24–7.27
(5H, m, Ph); 13C NMR: d 13.6* and 14.2 (OCH2CH3), 18.3*
and 19.0 (OCHCH3), 21.9 [OCH(CH3)2], 60.6 (OCH2CH3),
72.4 [OCH(CH3)2], 72.5 [CH2OCH(CH3)2], 72.5
(OCH2CH3), 80.9 and 81.4* (PhCH), 127.1 (C-2 of Ph),
127.9 (C-4 of Ph), 128.3 (C-3 of Ph), 139.5 (C-1 of Ph) and
173.3 (CO); de = 88%; MS (CI) m/z (rel. int.): 281 [MH]+
(5), 207 [MH ꢀ CH3OCHCH2]+ (10), 163 [MH ꢀ HOCH-
(CH3)CO2Et]+ (75), 121 [MH ꢀ CH3CH2CO2Et]+ (22), 58
[MH ꢀ PhCH(OH)CH2OCHCH2]+ (100); HRMS (CI) Calc.
for C16H25O4: 281.1753, Found 281.1762.
4.3.2.1. (R)-Ethyl-(2-isopropoxy-1-phenylethoxy)propano-
ate (R,R)-23. The product (215 mg, 87%) was isolated as a
colourless oil, [a]D20 = ꢀ82.8 (ca. 0.83, CH2Cl2), and had
spectroscopic data identical to 23.
4.3. General procedure B: preparation of methylated
benzyl alcohols (21 and 22)
4.3.2.2. (2R)-2-(10R)-(2-Isopropoxy-1-phenylethyl)oxypro-
panol (27). A solution of (R)-23 (180 mg, 0.642 mmol) in
THF (5 ml) was added to a suspension of lithium aluminium
hydride (24 mg, 0.642 mmol) in THF (10 ml). The mixture
was heated under reflux for 16 h before being quenched with
ethyl acetate and water. Filtration afforded the title product
(153 mg, 100%) as a colourless oil. IR (neat): n; 1H NMR: d
1.06 (3H, d, J = 6.1, CH3), 1.20 [3H, d, J = 6.1,
OCH(CH3)2], 1.22 [3H, d, J = 5.9, OCH(CH3)2], 3.46–
3.56 (3H, m, CH2OH, OCHCH3), 3.61–3.75 [3H, m,
OCH(CH3)2, CH2OCH(CH3)2], 4.72 (1H, dd, J = 3.6, 9.0,
PhCH), 7.28–7.38 (5H, m, Ph); 13C NMR: d 18.0 (CHCH3),
21.7 [OCH(CH3)2], 21.9 [OCH(CH3)2], 67.1 (CH2OH), 72.5
[OCH(CH3)2], 73.6 [OCH2(CH3)2], 77.6 (OCHCH3), 82.3
(PhCH), 126.3 (C-3 of Ph), 127.7 (C-4 of Ph), 128.3 (C-2 of
Ph), 140.0 (C-1 of Ph); MS (CI) m/z (rel. int.): 239 [MH]+
(12), [MH ꢀ Ph]+ (100); HRMS (CI) Calc. for C14H23O3:
239.1647, Found 239.1647.
A solution of LDA (2 M) in THF (49.5 mg, 0.462 mmol)
was slowly added to a solution of ethyl(2-alkoxy-pheny-
lethoxy)acetate 21–26 (100 mg, 420 mmol) in THF (3.0 ml)
at ꢀ78 8C. The solution was stirred for 30 min before methyl
iodide (72 mg, 0.507 mmol) was introduced. The reaction
was allowed to warm to ambient temperature and was stirred
for 12 h. The products were isolated by solvent extraction
and silica gel chromatography.
4.3.1. Ethyl-2-(2-methoxy-1-phenylethoxy)propanoate (22)
The product (75 mg, 68%) was isolated as a colourless
oil. IR (neat): n 2974, 1747, 1454, 1368, 1200, 1126, 912;
1H NMR: d 1.22 (3H, t, J = 7.2, OCH2CH3), 1.31 and
1.37* (3H, d, J = 6.9, OCHCH3), 3.32 (3H, s, OCH3), 3.38
(1H, dd, J = 4.1, 10.5, CH2OCH3), 3.63 (1H, dd, J = 7.2,
10.5, CH2OCH3), 3.81 (1H, q, J = 6.9, OCHCH3), 4.13
(2H, q, J = 7.2, OCH2CH3), 4.58 (1H, dd, J = 4.1, 7.2,
PhCH) and 7.26–7.27 (5H, m, Ph); 13C NMR: d 14.2
(CH2CH3), 18.2* and 19.0 (OCHCH3), 59.1 (OCH3), 60.7
(OCH2CH3), 72.3 (OCHCH3), 74.2 (CH2OCH3), 80.3
and 80.9* (PhCH), 127.1 (C-2 of Ph), 128.2 (C-4 of Ph),
128.5 (C-3 of Ph), 138.9 (C-1 of Ph) and 172.2 (CO);
MS (CI) m/z (rel. int.): 253 [MH]+ (338), 193 [HOCH2-
CO2Et ꢀ CH4]+ (100); HRMS (CI) Calc. for C14H20O4:
253.3062, Found 253.3059.
4.3.2.3. (2R)-2-(10R)-2-Isopropoxy-1-phenylethyloxypropa-
noic acid (28). Alcohol 27 (130 mg, 0.545 mmol) was
oxidised with Jones’s regent [CrO3, H2SO4 (50%),
acetone:water (3:1)] after stirring at ambient temperature
for 5 h. Isopropanol was added and the product was
isolated following solvent extraction and chromatography
to give carboxylic acid 28 (132 mg, 96%) as a colourless
oil. Treatment of 28 with morpholine (95 ml, 1.09 mmol)
in hexane (10 ml) afforded (R,R)-29 as a colourless
crystalline solid. 1H NMR: d 1.24 [3H, d, J = 6.1,
OCH(CH3)2], 1.27 [3H, d, J = 6.1, OCH(CH3)2],
1.45 (3H, d, J = 6.9, OCHCH3), 3.50–3.61 [2H, m,
OCH2CH], 3.79 [1H, sextet, J = 6.1, OCH(CH3)2], 3.99
(OCHCH3), 4.47 (1H, dd, J = 3.8, 9.2, PhCH), 7.31–7.42
4.3.2. Ethyl-2-(2-isopropoxy-1-phenylethoxy)propanoate
(23)
The product (74 mg, 85%) was isolated as a colourless
oil. IR (neat): n 2973, 1748, 1454, 1369, 1127; 1H NMR: d
0.99 [3H, d, J = 6.1, OCH(CH3)2], 1.04 [3H, d, J = 6.1,
OCH(CH3)2], 1.21 (3H, t, J = 7.2, OCH2CH3), 1.28 and
1.39* (3H, d, J = 6.9, OCHCH3), 3.41 [1H, dd, J = 5.4, 10.5,
CH2OCH(CH3)2], 3.46 [1H, dd, J = 5.4, 10.5, CH2-
OCH(CH3)2], 3.50 [1H, dd, J = 6.1, 10.5, CH2OCH(CH3)2],
(5H, m, Ph); 13C NMR:
d
19.4 (OCHCH3),
21.6 [OCH(CH3)2], 21.7 [OCH(CH3)2], 72.1 [OCH2-
CH(CH3)2], 73.2 [OCH(CH3)2], 75.0 (OCHCH3), 82.9
(PhCH), 126.4 (C-4 of Ph),128.7 (C-2/3 of Ph), 136.9 (C-1
of Ph), 174.8 (CO); MS (LCTOF) m/z (rel. int.): 275

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K. Tenza et al. / Journal of Fluorine Chemistry 125 (2004) 1779–1790
[MH + Na]+ (100); HRMS (CI) Calc. for C14H20O4Na:
275.1259, Found 275.1255.
128.6 (C-2 of Ph), 138.2 (C-1 of Ph); 19F NMR: d ꢀ220.8
(dt, J = 14.3, 46.7); MS (EI) m/z (rel. int.): 163.1 [M + Na]+
(100).
4.3.3. Ethyl-2-(2-tert-butoxy-1-phenylethoxy)propanoate
(24)
The product (86 mg, 82%) was isolated as a colourless
4.3.6. Ethyl(2-fluoro-1-phenylethoxy)acetate (12)
The product was prepared according to general procedure
A from 2-fluoro-1-phenylethanol 20 (260 mg, 1.86 mmol),
sodium hydride (211 mg, 5.58 mmol) and ethyl iodoacetate
(596 mg, 279 mmol) in THF (10 ml). The product (319 mg,
76%) was isolated as a colourless oil. IR (neat): n 2983,
1755, 1455, 1135; 1H NMR: d 1.17 (3H, t, J = 7.2, CH2CH3),
3.92 (1H, d, J = 16.4, OCH2CO), 4.05 (1H, d, J = 16.4,
OCH2CO), 4.10 (2H, q, J = 7.2, CH2CH3), 4.38 (1H, ddd,
J = 3.6, 9.7, J = 46.9, CH2F), 4.52 (1H, ddd, J = 7.4, 9.7,
46.9, CH2F), 4.71 (1H, ddd, J = 3.6, 7.4, 15.1, PhCH) and
7.50–7.31 (5H, m, Ph); 13C NMR: d 14.0 (OCH2CH3), 60.7
(OCH2CH3), 66.1 (OCH2CO), 80.8 (d, JCF = 19.6, PhCH),
85.5 (d, JCF = 173.5, CH2F), 127.2 (C-3 of Ph), 128.6 (C-4 of
Ph), 128.7 (C-2 of Ph), 135.7 (C-1 of Ph) and 169.9 (CO);
19F NMR: d ꢀ220.9 (dt, J = 15.1, 46.9); MS (CI) m/z (rel.
int.): 227 [MH]+ (82), 206 [MH ꢀ HF]+ (16), 123
[MH ꢀ HOCH2CO2Et]+ (63), 105 [MH ꢀ HOCH2-
HOCH2CO2Et ꢀ HF]+ (100); HRMS (CI) Calc. for
C12H16FO3: 227.1083, Found 227.1080.
1
oil: n 2974, 1736, 1450, 1377, 1198; H NMR: d 0.99 and
1.07* [9H, s, OC(CH3)3], 1.22 (3H, t, J = 7.2, OCH2CH3),
1.28 and 1.36* (3H, d, J = 6.9, OCHCH3), 3.36 (1H, dd,
J = 4.4, 9.5, CH2OCH3), 3.65 [1H, dd, J = 7.7, 9.5,
CH2OC(CH3)3], 3.87 (1H, q, J = 6.9, OCHCH3), 4.14
(2H, q, J = 7.2, OCH2CH3), 4.45 (1H, dd, J = 4.4, 7.7,
PhCH) and 7.24–7.27 (5H, m, Ph); 13C NMR: d 13.8* and
14.0 (OCH2CH3), 18.2* and 18.8 (OCHCH3), 27.2* and
27.1 (OC(CH3)3), 60.3* and 60.4 (OCH2CH3), 66.3 and
67.3* (CH2OCH3), 72.5 and 72.9* [OC(CH3)3], 74.4
(OCHCH3), 81.0 and 81.2* (PhCH), 126.7* and 127.0
(C-3 of Ph), 127.4*and 127.6 (C-4 of Ph), 127.8* and
127.9 (C-2 of Ph), 139.6* and 139.7 (C-1 of Ph) and 173.2
(CO); MS (CI) m/z (rel. int.): 295 [MH]+ (48), 239
[MH ꢀ CHCH3]+ (91), 207 [MH ꢀ CH3CO2C(CCH3]+
(46), 177 [MH ꢀ HOCH(CH3)CO2Et]+ (57), 119
[MH ꢀ HOCH(CH3)CO2Et]+ (100); HRMS (CI) Calc. for
C17H27O4: 295.1910, Found 295.1919.
4.3.4. 2-Fluoro-1-phenylethanone (19) [17]
4.3.7. Ethyl(2,2,2-trifluoro-1-phenylethoxy)acetate (13) [5]
The product was prepared according to general pro-
cedure A from 2,2,2-trifluoro-1-phenylethanol (200 mg,
1.14 mmol), ethyl iodoacetate (360 mg, 1.71 mmol) and
sodium hydride (55 mg, 2.28 mmol) in THF (10 ml). The
product was recovered (240 mg, 80%) as a colourless oil. IR
A solution of poly(hydrogen fluoride) (70/30) (3.0 ml)
was added to an ethereal solution of 2-oxo-2-phenyletha-
nediazonium at ꢀ15 8C, prepared in situ from benzoyl
chloride 18 (1.0 g, 7.11 mmol) and diazomethane. The
reaction was allowed to warm to room temperature and
stirred for 4 h under an inert atmosphere. Water (100 ml)
was added and after separation of the two phases, the
aqueous layer was extracted into hexane (3ꢁ 25 ml). The
organics were treated with anhydrous potassium fluoride
until neutral to litmus, dried over MgSO4 and concentrated
under reduced pressure. Purification over silica gel afforded
the product as a colourless oil (386 mg, 39%). IR (neat): n
3065, 2938, 1707, 1598, 1451, 1318, 1286, 1234, 1089; 1H
NMR: d 5.54 (2H, d, JHF = 46.8, CH2F), 7.46–7.96 (5H, m,
Ph); 13C NMR: d 83.7 (d, JCF = 182.4, CH2F), 127.7 (C-3 of
Ph), 128.8 (C-4 of Ph), 128.4 (C-2 of Ph), 134.1 (C-1 of Ph)
and 193.3 (d, JCF = 15.3, CO); 19F NMR d ꢀ231.5 (t,
J = 46.8); MS (EI) m/z (rel. int.): 160.6 [M + Na]+ (100).
1
(neat): n 2987, 1754, 1381, 1268, 1128; H NMR: d 1.25
(3H, t, J = 7.2, OCH2CH3), 4.03 (1H, d, J = 16.4, OCH2CO),
4.19 (1H, q, J = 7.2, OCH2CH3), 4.21 (1H, d, J = 16.4,
OCH2CO), 4.94 (1H, q, JHF = 6.4, PhCH) and 7.40–7.43
(5H, m, Ph); 13C NMR: d 14.0 (OCH2CH3), 61.1
(OCH2CH3), 66.0 (OCH2CO), 78.1 (q, JCF = 31.5, PhCH),
127.6 (q, JCF = 281.4, CF3), 128.4 (C-3 of Ph), 128.7 (C-2 of
Ph), 129.8 (C-4 of Ph), 131.5 (C-1 of Ph) and 169.2 (CO);
19F NMR: d ꢀ76.9 (d, JHF = 6.4, CF3); MS (CI) m/z (rel.
int.): 263 [MH]+ (100), 159 [MH ꢀ HOCH2CO2Et]+ (7);
HRMS (CI) Calc. for C15H13FO2: 263.0884, Found
263.0884.
4.3.8. Ethyl-2-(1-phenylethoxy)propanoate (21)
4.3.5. 2-Fluoro-1-phenylethanol (20)
The product was prepared using general procedure B
from ethyl(1-phenylethoxy)acetate 8 (105 mg, 0.504 m-
mol), LDA (2 M in THF) (64.8 mg, 0.605 mmol) and methyl
iodide (79 mg, 0.554 mmol) in THF (3.0 ml) to provide the
product ester as a colourless oil (78 mg, 70%). IR (neat): n
2983, 1736, 1453, 1377, 1208, 909; 1H NMR: d 1.09 (3H, t,
J = 7.2, OCH2CH3), 1.22 and 1.27 (3H, d, J = 6.9,
OCHCH3), 1.42 (3H, d, J = 6.4, PhCHCH3), 3.92 (1H, q,
J = 6.9, OCHCH3), 4.13 (2H, q, J = 7.2, OCH2CH3), 4.82
(1H, q, J = 6.4, PhCH), 7.18 (5H, m, Ph); 13C NMR: d 14.0
and 14.2 (OCH2CH3), 18.3 and 18.9 (OCHCH3), 60.6 and
The product was prepared by treatment of 2-fluoro-1-
phenylethanone 19 (300 mg, 2.14 mmol) with sodium
borohydride (240 mg, 6.42 mmol) in CH3OH (20 ml), to
give the title compound (301 mg, 99%) as a colourless oil.
IR (neat): n 3406, 2893, 1495, 1454, 1101, 1012; 1H NMR: d
2.58 (1H, br s, OH), 4.32 (1H, ddd, J = 8.0, 9.6, J = 46.7,
CH2F), 4.41 (1H, ddd, J = 3.3, 9.6, 46.7, CH2F), 4.91 (1H,
ddd, J = 3.3, 8.0, 14.3, PhCH) and 7.23–7.30 (5H, m, Ph);
13C NMR: d 72.9 (d, JCF = 19.9, PhCH), 87.1 (d,
JCF = 174.2, CH2F), 126.3 (C-3 of Ph), 128.3 (C-4 of Ph),

K. Tenza et al. / Journal of Fluorine Chemistry 125 (2004) 1779–1790
1787
61.7 (OCH2CH3), 71.9 and 72.9 (OCHCH3), 77.2 and 77.3
(PhCH), 125.3, 126.2, 127.6, 128.4, 128.5, 143.1, 173.7; MS
(EI) m/z (rel. int.): 246 [M + Na]+ (100); HRMS (EI) Calc.
for C13H18O3: 246.2802, Found 246.2715.
(132 mg, 2.10 mmol). The mixture was allowed to stir for
17 h at rt. The solvent was removed under reduced pressure,
before addition of water (50 ml) followed by potassium
hydroxide (1 M) solution until the solution was strongly
alkaline. The aqueous phase was saturated with sodium
chloride before being extracted into ether (3ꢁ 20 ml). The
combined ethereal extracts were washed with 20% ferrous
sulfate (aq.) (2ꢁ 20 ml), dried over MgSO4 and concen-
trated. The crude product was dissolved in hexane and
purified over silica gel, yielding benzylamine 29 (230 mg,
82%) as a white amorphous solid: m.p., 114–115 8C;
[a]D20 = +64 (ca. 0.62, CH2Cl2); IR (KBr): n 3319, 3026,
2952, 1491, 1451; 1H NMR: d 0.76 [3H, d, J = 6.8,
CH(CH3)2]; 0.93 [3H, d, J = 6.9, CH(CH3)2]; 1.69 (1H, m,
H-3), 3.19 (1H, dd, J = 6.1, 10.5, H-2), 3.20 (1H, d, J = 12.3,
PhCH2N), 3.46 (1H, d, J = 12.3, PhCH2N), 3.70 (1H, d,
J = 10.5, H-1), 6.89–7.36 (10H, m, Ph); 13C NMR: d 16.1
[CH(CH3)2], 21.8 [CH(CH3)2], 30.5 (C-3), 56.2 (PhCH2N),
57.4 (C-1), 66.5 (C-2), 126.6, 126.8, 127.6, 128.5, 128.6,
128.8, 129.1, 142.6, 144.1 (aromatic carbons); MS (CI) m/z
(rel. int.): 330 [MH+] (100), 240 [MH ꢀ PhCH2)]+ (6), 162
[MH ꢀ Ph2CH2]+ (58); HRMS (CI) Calc. for C24H28N:
330.2222, Found 330.2217.
4.3.9. Ethyl-2-(2-fluoro-1-phenylethoxy)propanoate (25)
The product was prepared according to general
procedure B from ethyl (2-fluoro-1-phenylethoxy)acetate
12 (129 mg, 0.570 mmol), LDA (2 M in THF) (67 mg,
0.628 mmol) and methyl iodide (202 mg, 3.56 mml) in
THF (5.0 ml). The product (79 mg, 58%) was isolated to as
1
a colourless oil. IR (neat): n 2985, 1747, 1455, 1122; H
NMR: d 1.13* and 1.29 (3H, t, J = 7.2, OCH2CH3), 1.40
and 1.46* (3H, d J = 6.9, OCHCH3), 3.92 (1H, q, J = 6.9,
OCHCH3), 4.17* and 4.20 (1H, q, J = 7.2, OCH2CH3),
4.44 (1H, ddd, J = 3.8, 9.7, 46.9, CH2F), 4.57 (1H, ddd,
J = 9.7, 9.7, 46.9, CH2F), 4.74 (1H, ddd, J = 3.8, 10.5,
15.6, PhCH) and 7.32–7.39 (5H, m, Ph); 13C NMR: d 14.0*
and 14.2 (OCH2CH3), 18.2* and 18.9 (CHCH3), 60.7*
and 60.9 (OCH2CH3), 72.8 (OCHCH3), 80.5
(d, JCF = 20.7, PhCH), 85.5 and 86.0* (d, JCF = 177,
CH2F), 127.2 (C-3 of Ph), 128.4 (C-4 of Ph), 128.7 (C-2
of Ph), 136.6 (C-1 of Ph), 172.5* and 172.9 (CO);
19F NMR: d ꢀ219.1*and ꢀ221.6 (dt, J = 15.6, 46.9);
MS (CI) m/z(rel. int.): 241 [MH]+ (82), 220 [MH ꢀ HF]+
(12), 123 [MH ꢀ HOCH(CH3)CO2Et]+ (57), 119
[MH ꢀ PhCH2CH2F]+ (100); HRMS (CI) Calc. for
C13H18FO3: 241.1239, Found 241.1239.
4.4.2. (S)-Ethyl-2-[N-benzyl-N-((10S)-1-diphenylmethyl-2-
methylpropyl)]amino-2-oxoacetate (32)
Triethylamine (158 mg, 1.56 mmol) was added to a
stirred solution of N-benzylamine 31 (174 mg, 0.53 mmol)
in CH2Cl2 (3.0 ml) at ꢀ78 8C. The reaction was stirred for
15 min and then ethyl oxalyl chloride (110 mg, 0.79 mmol)
was added. The reaction was allowed to warm to ambient
temperature and was stirred for a further 4 h. Following
standard work-up, the crude product was purified over silica
gel to give the title compound (890 mg, 92%) as a white
crystalline solid: m.p., 117–119 8C; [a]D20 = ꢀ9.3 (ca. 0.62,
4.3.10. Ethyl-2-(2,2,2-trifluoro-1-phenylethoxy)
propanoate (26) [5]
The product was prepared according to general procedure
B from 13 (158 mg, 0.60 mmol), LDA (2 M in THF)
(70.9 mg, 0.66 mmol) and methyl iodide (94 mg,
0.66 mmol) in THF (5.0 ml). The product (110 mg, 66%)
was isolated as a colourless oil. IR (neat): n 2987, 1754,
1382, 1269, 1127; 1H NMR: d 1.17 (3H, J = 7.2, OCH2CH3),
1.36 and 1.42* (3H, d, J = 6.9, OCHCH3), 3.86 (1H, q,
J = 6.9, OCHCH3), 4.13 (2H, q, J = 7.2, OCH2CH3), 4.85
(1H, q, JHF = 6.4, PhCH), 7.18–7.36 (5H, m, Ph); 13C NMR:
d 13.9 (OCH2CH3), 31.0 (OCHCH3), 61.0 (OCH2CH3), 65.9
(OCHCH3), 79.26 (q, JCF = 31.5, PhCH), 127.1 (q,
1
CH2Cl2), IR (KBr): n 2960, 1727, 1631, 1427, 1175; H
NMR: d 0.78 (3H, m, OCH2CH3), 0.93 [3H, d, J = 6.9,
CH(CH3)2], 0.94 [3H, d, J = 6.9, CH(CH3)2], 1.79 (1H, m,
H-2), 3.47 (1H, dq, J = 7.5, 10.8, OCH2CH3), 3.52 (1H, dq,
J = 7.2, 10.8, OCH2CH3), 4.23 (1H, d, J = 13.5, NCH2Ph),
4.32 (1H, d, J = 12.3, CHPh2), 4.28 (1H, d, J = 13.5,
NCH2Ph), 5.68 (1H, dd, J = 12.3, 12.6, H-2), 6.54–7.37
(15H, m, Ph); 13C NMR: d 13.8 (OCH2CH3), 17.8
[CH(CH3)2], 20.9 [CH(CH3)2], 31.0 (C-2), 49.67 (NCH2Ph),
53.8 (CHPh2), 61.9 (C-1), 62.7 (OCH2CH3), 127.2, 127.6,
128.1, 128.2, 128.6, 129.2, 129.4, 129.5, 136.7, 142.0,
142.5, 143.1 (aromatic carbons), 163.1 (NCOCO2Et), 164.8
(NCOCO2Et); MS (CI) m/z (rel. int.): 430 [MH]+ (100), 75
[(CH3)2CHNH2]+ (76); HRMS (CI): Calc. for C28H32NO3:
430.2382, Found 430.2392.
J
CF = 281.4, CF3), 128.3 (C-2 of Ph), 128.4 (C-3 of Ph),
128.6 (C-4 of Ph), 131.5 (C-1 of Ph), 169.1 (CO); 19F NMR:
d ꢀ76.9 and ꢀ78.9 (d, JHF = 6.4, CF3); MS (CI) m/z (rel.
int.): 277 [MH]+ (100); HRMS (CI) Calc. for C13H16F3O3:
277.1052, Found 277.1049.
4.4. More complex systems
4.4.1. (S)-N-Benzyl-3-methyl-1,1-diphenyl-2-butanamine
(31)
Methanolic HCl was added to a solution of isopropy-
lamine 30 (204 mg, 0.85 mmol) in methanol (3.0 ml), so as
to adjust the pH to 6.3. Benzaldehyde (115 mg, 1.08 mmol)
was then added followed by sodium cyanoborohydride
4.4.3. (S)-2-[N-Benzyl-N-((10S)-diphenylmethyl-2-
methylpropyl)]aminoethanoic acid (33)
Sodium hydroxide (25.0 mg, 0.65 mmol) was added to a
solution of 32 (281 mg, 0.65 mmol) in ethanol/THF solution
(1:3). The reaction was stirred at rt for 15 h, and then the

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K. Tenza et al. / Journal of Fluorine Chemistry 125 (2004) 1779–1790
solvents were evaporated under reduced pressure, yielding
the sodium carboxylate as an amorphous solid. The salt
(164 mg, 0.38 mmol) was dissolved in THF (5.0 ml), and
charged into a flask containing diborane (1.5 M in THF,
0.51 ml, 0.76 mmol) at 0 8C. The reaction mixture was
heated under reflux for 15 h and then the mixture was cooled
to rt, and subsequently quenched with glacial acetic acid
(1.0 ml). The solvent was removed under reduced pressure
and the crude product purified over silica gel to give
carboxylic acid 33, as a white amorphous solid; m.p.: 148–
150 8C; IR (KBr): n 3430 (COOH), 1770 (CO), 1638, 1493,
solvent was evaporated and then ether (10 ml) was added,
and the products were extracted from water (30 ml). The
combined ethereal layer was evaporated. The diastereoi-
somers were separated over silica gel and the major
diastereoisomer recovered (84.3 mg, 68%). Data for the
major diastereoisomer [a]D20 = +21 (ca. 0.81, CH2Cl2); IR
1
(neat): n 2929, 1735 (CO), 1452, 1261, 1147; H NMR: d
0.50 (3H, d, J = 7.2, NCHCH3), 0.82 [3H, d, J = 7.2,
CH(CH3)2], 0.89 [3H, d, J = 6.9, CH(CH3)2], 2.13 (1H, m,
H-2), 3.50 (1H, q, J = 7.2, NCHCH3), 3.59 (3H, s, OCH3),
3.63 (1H, m, H-1), 3.89 (1H, d, J = 14.1, PhCH2N), 3.96
(1H, d, J = 14.1, PhCH2N), 4.10 (1H, d, J = 11.4, CHPh2),
6.92–7.25 (15H, m, Ph); 13C NMR: d 18.5 [CH(CH3)2], 19.3
[CH(CH3)2], 23.8 (NCHCH3), 29.3 (C-2), 51.4 (OCH3),
51.4 (PhCH2N), 53.9 (C-1), 54.6 (NCH2CO), 62.5 (CHPh2),
126.1, 126.7, 127.2, 128.2, 128.3, 128.7, 129.0, 129.1,
130.5, 140.1, 144.4, 144.8 (aromatics carbons), 176.7 (CO);
MS (CI) m/z (rel. int.): 417 [MH]+ (100), [MH ꢀ Ph2CH2]+
(42); HRMS (CI) Calc. for C28H34NO2: 415.5672, Found
415.5668.
1
1454, 1337; H NMR: d 0.68 [3H, d, J = 7.2, CH(CH3)2],
0.90 [3H, d, J = 6.9, CH(CH3)2], 2.02 (H, m, NCH), 3.35
(2H, br, NCH2CO2H), 3.55 (2H, br, NCH2Ph), 3.65 (1H, dd,
J = 11.7, 11.7, H-1), 4.15 (1H, d, J = 11.7, CHPh2), 7.01–
7.26 (15H, m, Ph); 13C NMR: d 20.4 [CH(CH3)2], 28.9
(CHPh2), 54.0 (C-1), 54.7 (NCH2Ph), 60.7 (NCH2CO2H),
127.3, 127.6, 128.6, 128.7, 128.9, 129.1, 129.2, 129.6,
130.4, 136.1, 142.8, 143.1 (aromatic carbons), 171.8
(CH2CO2H); MS (CI) m/z (rel. int.): 388 [MH]+ (100),
344 [MH ꢀ CO2H]+ (15), 220 [MH ꢀ Ph2CH]+ (48);
HRMS (CI) Calc. for C26H30NO2: 388.2277, Found
388.2283.
4.4.6. (2R)-Methyl-2-[(10S)-N-diphenylmethyl-2-
methylpropyl]aminopropanoate (37) and
hydrochloride (38)
4.4.4. (S)-Methyl 2-[N-benzyl-N-diphenylmethyl-(2-
methylpropyl)]aminoacetate (34)
Pearlman’s catalyst (30 mg) was added to a solution of 36
(100 mg, 0.241 mmol) in methanol (50 ml). The reaction
vessel was pressurised with hydrogen (10 bar). After 10 h
the pressure was released and the reaction filtered and the
solvent removed to afford the product (77 mg, 99%) as a
colourless oil. Treatment of 37 with anhydrous HCl provided
the hydrochloride salt 38 in quantitative yield. Data for 37
[a]D20 = +62 (ca. 0.77, CH2Cl2); IR (neat): n 2963, 2947,
A solution of diazomethane in ether was added to a
solution of carboxylic acid 33 (139 mg, 0.36 mmol) in ether
until the yellow diazomethane solution persisted. Glacial
acetic acid was then added until the yellow solution turned
colourless. The ethereal solution was evaporated in vacuo to
obtain the methyl ester 34 (144 mg, 100%) as a pale yellow
oil. [a]D20 = +4.8 (ca. 0.78, CH2Cl2); IR (KBr): n 2965,
1
1714, 1495, 1451, 1214, 1152; H NMR: d 0.71 [3H, d,
1
1709, 1494, 1363, 1222; H NMR: d 0.72 [3H, d, J = 7.2,
J = 6.9, CH(CH3)2], 0.89 [3H, d, J = 7.2, CH(CH3)2], 1.03
(3H, d, J = 6.9, NCHCH3), 1.64–4.73 (1H, m, H-2), 2.94
(1H, q, J = 6.9, NCHCH3), 3.20 (1H, dd, J = 2.3, 10.5, H-1),
3.45 (3H, s, OCH3), 3.74 (1H, d, J = 10.5, CHPh2), 7.05–
7.32 (10H, m, Ph); 13C NMR: d 19.9 [CH(CH3)2], 21.2
[CH(CH3)2], 21.3 [CH(CH3)2], 29.3 (NCHCH3), 55.7 (C-1),
57.2 (NCH), 63.4 (OMe), 63.4 (CHPh2), 126.2, 126.4, 128.2,
128.4, 128.5, 128.6 (C of Ph), 142.8, 143.6 (C-1 of Ph),
175.6 (CO); MS (CI) m/z (rel. int.): 326 [MH]+ (100),
[MH ꢀ Ph2CH2]+ (167); HRMS (CI) Calc. for C21H28NO2:
326.2120, Found 326.2118.
CH(CH3)2], 0.90 [3H, d, J = 6.9, CH(CH3)2], 1.77 (1H, m,
H-2), 3.13 (1H, d, J = 16.8, NCH2CO), 3.40 (1H, d, J = 16.8,
NCH2CO), 3.41 (3H, s, OCH3), 3.56 (1H, d, J = 13.2,
PhCH2N), 3.63 (1H, d, J = 13.2, PhCH2N), 3.62 (1H, dd,
J = 11.40, 12.0, H-1), 4.17 (1H, d, J = 11.4, CHPh2), 6.95–
7.99 (15H, m, Ph); 13C NMR: d 18.6 [CH(CH3)2], 21.5
[CH(CH3)2], 30.6 (C-2), 51.6 (OCH3), 54.1 (PhCH2N), 55.0
(NCH2CO), 68.5 (CHPh2), 126.7, 127.2, 128.2, 128.5,
128.7, 128.9, 129.0, 129.3, 130.0, 139.6, 144.5, 144.6
(aromatic carbons); 173.3 (CO); MS (CI) m/z (rel. int.): 402
[MH]+ (100), [MH ꢀ Ph2CH2]+ (46); HRMS (CI) Calc. for
C27H32NO2: 402.2433; Found 402.2445.
4.4.7. (2S)-N-Benzyl-1-fluoro-3-methyl-1,1-diphenyl-2-
butanamine (40)
Methanolic HCl was added to a solution of (S)-a-
4.4.5. (2R)-Methyl-2-[N-benzyl-N-((10S)-diphenylmethyl-
2-methylpropyl)]aminopropanoate (36)
fluorodiphenylmethyl
isopropylamine
39
(1.00 g,
A solution of methyl ester 34 (119 mg, 0.30 mmol) in
THF (15 ml) was added to a LDA/THF preparation:
[diisopropylamine (33.1 mg, 0.33 mmol) and n-BuLi
(2.5 M in hexane), 150 ml, 0.39 mmol at 0 8C solution at
ꢀ50 8C]. Methyl iodide (42.2 mg, 0.30 mmol) was then
added and the reaction was allowed to warm to rt over 1 h
and was further stirred at ambient temperature for 8 h. The
3.86 mmol) in CH3OH (50 ml), and the pH adjusted to
6.6. Benzaldehyde (537 mg, 5.06 mmol) was then intro-
duced followed by sodium cyanoborohydride (733 mg,
11.7 mmol). The procedure used in Section 4.4.1 was
followed. Chromatographic purification of the crude mixture
yielded amine 40 (686 mg, 50%) as a white amorphous
solid: m.p. = 90–92 8C; [a]D20 = ꢀ38 (ca. 0.80, CH2Cl2); IR

K. Tenza et al. / Journal of Fluorine Chemistry 125 (2004) 1779–1790
1789
(KBr): n 3314, 3026, 2956, 1494, 1449, 1326, 1098, 980,
704; 1H NMR: d 0.81 [3H, d, J = 6.9, CH(CH3)2], 0.92 [3H,
d, J = 7.0, CH(CH3)2], 1.52 (1H, br NH), 1.79 (1H, m, H-3),
3.45 (1H, dd, JHF = 31.9, H-2), 4.55 (2H, s, NCH2Ph), 7.10–
7.41 (15H, m, Ph); 13C NMR: d 17.0 [CH(CH3)2], 23.1
[CH(CH3)2], 29.8 (C-3), 55.2 (NCH2Ph), 68.1 (d,
69.3 (d, JCF = 19.3, NCH), 104.9 (d, JCF = 188.5), 124.2,
124.4, 124.8, 125.0, 126.9, 127.0, 127.1, 128.1, 128.2,
144.3, 144.4, 144.7; 19F NMR: d ꢀ169.3 (d, JHF = 36.8); MS
(CI) m/z (rel. int.) 392 [MH]+ (100), 374 [MH ꢀ H2O]+ (8),
206 [MH ꢀ Ph2CHF]+ (29); HRMS (CI) Calc. for
C26H31FNO: 392.2389, Found 392.2387.
J
CF = 21.0, C-2), 102.9 (d, JCF = 183.0, C-1), 124.96,
125.0, 125.2, 126.7, 127.1, 127.2, 128.0, 128.3, 140.9,
143.1, 143.2, 143.5 (aromatic carbons); 19F NMR: d ꢀ168.2
(d, JHF = 31.9); MS (CI) m/z (rel. int.): 348 [MH]+ (43), 258
[MH ꢀ Ph2CH]+ (100), 72 [Ipr ꢀ CHNH2] (58); HRMS
(CI) Calc. for C24H27FN: 348.2127, Found 348.2108.
4.4.10. Methyl[(10S)-N-benzyl-N-fluorodiphenylmethyl-2-
methylpropyl]aminoethanoate (43)
A solution of alcohol 42 (95 mg, 0.245 mmol) in
CH2Cl2 (1.0 ml) was added to a flask containing Dess-
Martin periodinate (103 mg, 0.243 mmol) in CH2Cl2
(2.0 ml). After 20 min, a saturated solution of sodium
bicarbonate was added and the organics were then washed
with sodium thiosulfate solution (10%). The combined
aqueous extract was washed with ether (2ꢁ 10 ml) and
then evaporation of the organics under reduced pressure
gave the corresponding aldehyde (95 mg, 100%), which
was used directly.
4.4.8. 2-[(10S)-N-Benzyl-N-1-(fluorodiphenylmethyl)-2-
methylpropyl]amino-2-oxoethanoate (41)
A solution of N-benzylamine 40 (471mg, 1.36 mmol) in
CH2Cl2 (15 ml) was treated with triethylamine (413 mg,
4.08 mmol) and ethyl oxalylchloride (241 mg, 1.77 mmol)
in CH2Cl2 (15 ml) as described under Section 4.4.2.
Purification over silica gel afforded the title compound 41
(586 mg, 96%), as a white amorphous solid: m.p., 117–
120 8C; [a]D20 = ꢀ9.6 (ca. 0.60, CH2Cl2); IR (KBr): n 2968,
1734, 1656, 1451, 1311, 1265, 1198; 1H NMR: d 0.83 [3H, d,
J = 6.9, CH(CH3)2], 0.88 [3H, m, CH(CH3)2], 1.25 (3H, t,
J = 7.2, OCH2CH3), 1.89–1.99 [1H, m, CH(CH3)2], 4.47
(1H, d, J = 7.2, NCH2Ph), 4.49 (1H, d, J = 7.2, NCH2Ph),
4.15 (1H, dq, J = 7.2, 10.2, OCH2CH3), 4.23 (1H, dq,
J = 7.2, 10.2, OCH2CH3), 4.98 (1H, ddd, J = 2.2, 10.6, 35.9),
7.09–7.47 (15H, m, Ph); 13C NMR: d 14.3 (OCH2CH3), 17.3
[CH(CH3)2], 17.4 [CH(CH3)2], 22.5 [CH(CH3)2], 29.2
(C-3), 58.7 (d, JCF = 18.6, C-2), 63.7 (OCH2CH3), 67.5
(NCH2Ph), 102.3 (d, J = 183.3, CFPh2), 124.5, 124.6, 124.8,
125.0, 126.1, 128.1, 128.4, 128.8, 129.1, 129.6, 142.0, 142.3
(aromatic carbons), 157.0 (NCOCO2Et), 160.7 (NCO-
CO2Et); 19F NMR: d ꢀ168.7 (d, JHF = 35.9); MS (CI)
m/z (rel. int.): 449 [MH]+ (80), 429 [MH ꢀ HF]+ (100), 263
[MH ꢀ Ph2CHF] (16); HRMS (CI) Calc. for C28H29FNO3:
450.2127, Found 450.2108.
To a stirred solution of the aldehyde (95 mg, 0.243 mmol)
in t-butanol (8.0 ml) and 2-methyl-2-butene (2.0 ml) was
added a solution of NaClO2 (250 mg, 2.19 mmol) and
NaH2PO4 (403 mg, 1.70 mmol) in water (2.5 ml). The
reaction was allowed to stir at ambient temperature for
40 min, whereupon water (10 ml) and ethyl acetate (30 ml)
were added. The phases were separated, and the organic
layer was washed with saturated NaCl solution (10 ml),
dried over MgSO4, filtered, and concentrated in vacuo. The
residue was dissolved in methanol (5.0 ml) and was treated
with TMS–diazomethane (2 M in hexane) (0.15 ml,
0.292 mmol). The methanol was removed under reduced
pressure and the crude product purified over silica gel to give
the title compound (31 mg, 30%) as a colourless oil.
[a]D20 = +5.9 (ca. 0.63, CH2Cl2); IR (neat): n 2926, 1751,
1
1449, 1277, 1199, 1169, 1030; H NMR: d 0.73 [3H, d,
J = 6.9, CH(CH3)2], 0.97 [3H, d, J = 6.9, CH(CH3)2], 2.10
(1H, m, H-2), 3.33 (1H, d, J =17.4, NCH2CO), 3.44 (3H, s,
OCH3), 3.48 (1H, d, J = 13.3, NCH2Ph), 3.60 (1H, d,
J = 13.3, NCH2Ph), 3.72 (1H, dd, J = 3.1, JHF = 37.1, H-1),
3.84 (1H, d, J = 17.4, NCH2CO), 7.09–7.48 (15H, m, Ph);
13C NMR: d 19.2 [CH(CH3)2], 23.0 [CH(CH3)2], 28.9 (C-2),
51.2 (OCH3), 53.9 (NCH2Ph), 58.9 (NCH2CO), 69.3 (d,
2JCF = 19.4, C-2), 104.5 (d, JCF = 186.9, C-1), 124.2, 124.4,
125.1, 125.3, 127.0, 127.7, 127.9, 128.0, 128.8, 130.0,
141.3, 144.6, 173.0 (CO); 19F NMR: d ꢀ168.3 (d,
4.4.9. 2-[(10S)-N-Benzyl-N-(1-fluorodiphenylmethyl-2-
methylpropyl)]aminoethanol (42)
A solution of ester 41 (350 mg, 0.78 mmol) in THF was
slowly added to a suspension of lithium aluminium hydride
(58 mg, 1.56 mmol) in THF at rt. The reaction was heated
under reflux for 30 min. Excess hydride was quenched by the
cautious addition of water. The organics were filtered and
the solvent removed under reduced pressure to give alcohol
42 (306 mg, 100%) as a white amorphous solid: m.p.,
90–91 8C; [a]D20 = +5.6 (ca. 0.69, CH2Cl2); IR (KBr): n
3423, 2956, 1599, 1493, 1450, 1047; 1H NMR: d 0.94 [3H, d,
J = 7.2, CH(CH3)2], 0.96 [3H, dd, J = 1.5, 7.2, CH(CH3)2],
2.27 (1H, m, H-2), 2.85 (2H, m, NCH2CH2OH), 3.16–3.27
(4H, m, NCH2Ph and NCH2CH2OH), 3.72 (1H, dd, J = 3.3,
J
HF = 37.1); MS (CI) m/z (rel.): 420 [MH]+ (100), 400
[MH ꢀ HF]+ (8), 234 [MH ꢀ Ph2CHF]+ (14); HRMS (CI)
Calc. for C27H31FNO2: 420.2338, Found 420.2335.
4.4.11. (2R)-Methyl-2-[(10S)-benzyl-N-(1-
fluorodiphenylmethyl-2-methylpropyl)]aminopropanoate
(45)
Methylation of ester 43 (54 mg, 0.129 mmol) followed
the procedure outlined in Section 4.4.5. The product was
purified over silica gel to give a 2:1 mixture of
diastereoisomers as a colourless oil. IR (neat): n 2930,
J
HF = 36.8, H-1), 7.09–7.36 (15H, m, Ph); 13C NMR: d 22.6
[CH(CH3)2], 23.3 [CH(CH3)2], 29.8 [CH(CH3)2], 57.0
(NCH2CH2OH), 59.9 (NCH2CH2OH), 67.9 (NCH2Ph),

1790
K. Tenza et al. / Journal of Fluorine Chemistry 125 (2004) 1779–1790
1
1738 (CO), 1493, 1384, 1262, 1148; H NMR: d 0.73 [d,
J = 6.9, CH(CH3)2], 0.97 [d, J = 6.9, CH(CH3)2], 1.28 (d,
J = 6.7, NCHCH3), 1.30* (d, J = 6.7, NCHCH3), 2.00 (1H,
m, H-2), 3.45 (3H, s, OCH3), 3.48 (1H, q, J = 6.7,
NCHCH3), 3.50 (1H, d, J = 13.6, NCH2Ph), 3.59 (1H, d,
J = 13.6, NCH2Ph), 3.72 (1H, dd, J = 3.1, J = 37.1, H-1),
7.01–7.48 (15H, m, Ph); 13C NMR: d 18.1 [CH(CH3)2], 18.8
[CH(CH3)2], 23.4 (NCHCH3), 28.9 (C-2), 51.0 (OCH3),
53.9 (NCHCH3), 65.8 (NCH2Ph), 69.3 (d, JCF = 19.4, C-1),
105.6 (d, JCF = 186.9, CFPh2), 124.3, 124.4, 125.1, 125.3,
127.0, 127.8, 128.4, 130.0, 139.7, 144.0, 144.3, 176.3 (CO);
19F NMR: d ꢀ168.3 (d, JHF = 37.1); MS (CI) m/z (rel. int.):
434 [MH]+ (100), 414 [MH ꢀ HF]+ (10); HRMS (CI) Calc.
for C28H32FNO2: 434.5576, Found 434.5570.
4.4.11.3. Crystal data for 38. C24H23N, M = 370.90,
˚
tetragonal, space group P4(1), a = 10.1769(15) A,
3
˚
˚
˚
b = 10.1769(15) A, c = 40.051(9) A, V = 4148.0(12) A ,
T = 125(2) K, Z = 8, m(Mo Ka) = 0.200 mmꢀ1, colourless
block, crystal dimensions, 0.1 mm ꢁ 0.04 mm ꢁ 0.02 mm.
Full-matrix least-squares based on F2 gave R1 = 0.1021 for
7564 observed (F > 4s(F) and wR2 = 0.2803 for all data),
GOF = 0.993 for 479 parameters.
References
[1] D.A. Evans, in: J.D. Morrison (Ed.), Asymmetric Synthesis, vol. 3,
Academic Press, New York, 1984 (Chapters 1 and 2).
[2] D.A. Evans, M.D. Ennis, D.J. Mathre, J. Am. Chem. Soc. 104 (1982)
1737–1739.
4.4.11.1. Crystal structure determination of 29 and
36. Data for both compounds were measured on a Bruker
SMART diffractometer with graphite monochromated
Mo Ka radiation (l = 0.7107) using a 0.38 width steps
accumulating area detector frames spanning a hemisphere of
reciprocal space for both structures; the reflections were
corrected for Lorentz and polarisation effects. Absorption
effects were corrected on the basis of multiple equivalent
reflections. The structures were solved by direct methods
and refined by full-matrix least-squares on F2 using the
program SHELXTL. All hydrogen atoms were included in
calculated positions using a riding model. All non-hydrogen
atoms were refined as anisotropic.
[3] G.A. Kraus, M.J. Taschner, Tetrahedron Lett. 18 (1977) 4575–
4578.
[4] C.H. Heathcock, M.C. Pirrung, J. Lampe, C.T. Buse, S.D. Young, J.
Org. Chem. 46 (1981) 2290–2300.
[5] M. Zuger, Th. Weller, D. Seebach, Helv. Chim. Acta 63 (1980) 2005–
2009.
[6] D. Seebach, D. Wasmuth, Helv. Chim. Acta 63 (1980) 197–200.
[7] T. Yamazaki, S. Hiraoka, T. Kitazume, J. Org. Chem. 59 (1994) 5100–
5103.
[8] C.-P. Qiana, T. Nakai, J. Am. Chem. Soc. 112 (1990) 4602–4606.
[9] T. Morizawa, A. Yasuda, K. Uchida, Tetrahedron Lett. 17 (1986)
1833–1836.
[10] T. Yamazaki, J. Haga, T. Kitazume, Chem. Lett. (1991) 1974–2171.
[11] S.S. Wong, M.N. Paddon-Row, J. Chem. Soc., Chem. Commun.
(1991) 327–330.
[12] J.A.K. Howard, V.J. Hoy, D. O’Hagan, G.T. Smith, Tetrahedron 52
(1996) 12613–12622.
4.4.11.2. Crystal data for 29. C18H29NO5, M = 339.42,
monoclinic,
[13] J.D. Dunitz, R. Taylor, Chem. Eur. J. 3 (1997) 89–98.
[14] T. Yamazaki, M.T. Kitazume, T. Kubota, M. Omura, Org. Lett. 1
(1999) 905–908.
˚
a = 25.418(4) A,
space
group
C2,
˚
˚
b = 6.5104(9) A, c = 11.3405(16) A, b = 101.540(2)8,
3
V = 1838.7(4) A , T = 125(2) K, Z = 4, m(Mo Ka) =
˚
[15] A.W. Williamson, J. Chem. Soc. 4 (1852) 106–107.
[16] W. Reeve, I. Christoffel, J. Am. Chem. Soc. 72 (1950) 1480–1483.
[17] G.A. Olah, J.T. Welch, Y.D. Vankar, M. Nojima, I. Kerekes, J.A. Olah,
J. Org. Chem. 44 (1979) 3872–3881.
0.089 mmꢀ1
,
colourless block, crystal dimensions,
0.12 mm ꢁ 0.1 mm ꢁ 0.02 mm. Full-matrix least-squares
based on F2 gave R1 = 0.0345 for 3120 observed (F > 4s(F)
and wR2 = 0. 0867 for all data), GOF = 1.026 for 226
parameters.
[18] M. Vincent, J. Duhault, M. Boulanger, G. Remond, DE Patent
2,843,776 (1979).
[19] I. Yusuke, H. Kyoji, Chem. Lett. (1980) 787–792.