A practical entry to β-aryl-β-alkyl amino alcohols: Application to the synthesis of a potent BACE1 inhibitor

Article abstract of DOI:10.1039/c2ob25845e

The 1,2-addition of alkyl Grignard reagents to readily available N-tert-butanesulfinyl ketimines, bearing an α-silyloxy substituent, proceeds in high yields and excellent diastereocontrol. The utility of the present method was demonstrated by the synthesi

Full text of DOI:10.1039/c2ob25845e

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PAPER
A practical entry to β-aryl-β-alkyl amino alcohols: application to the
synthesis of a potent BACE1 inhibitor†
Oscar Delgado,*a Antonio Monteagudo,b Michiel Van Gool,a Andrés A. Trabancoa and Santos Fustero*b,c
Received 3rd May 2012, Accepted 21st June 2012
DOI: 10.1039/c2ob25845e
The 1,2-addition of alkyl Grignard reagents to readily available N-tert-butanesulfinyl ketimines, bearing
an α-silyloxy substituent, proceeds in high yields and excellent diastereocontrol. The utility of the present
method was demonstrated by the synthesis, in enantiomerically pure form, of one recently disclosed
β-secretase (BACE1) inhibitor.
Introduction
The inhibition of β-secretase (BACE1) is believed to represent a
potential disease modifying treatment for Alzheimer’s disease
(AD).1 AD is characterized by two major central nervous system
pathologies: the occurrence of neurofibrillar tangles and amyloid
plaques. These insoluble plaques are formed after the aggrega-
tion of β-amyloid (Aβ) peptides of 39–43 amino acids which are
formed via the sequential cleavage of β-amyloid precursor
protein (APP) by β- and γ-secretase.2–5 Many of the on-going
efforts in the pharmaceutical industry are based on an anti-
amyloid approach, aimed at increasing Aβ-clearance or decreas-
ing Aβ-production and aggregation. The disclosure of a series of
thioguanidines6 and aminopyrimidones7 as potent BACE1
Fig. 1 BACE1 inhibitors containing the tertiary carbinamine motif.
inhibitors displaying in vivo efficacy has paved the way for the
identification of drug-like and brain penetrant ligands for this
biological target. From our internal medicinal chemistry
to avoid the complicating factors, which may be present when
program, we have recently disclosed a racemic synthesis of
using racemates in drug discovery programs,11 having access to
aminopiperazinone inhibitors displaying submicromolar acti-
enantiomerically pure compounds was deemed essential. It was
vities (Fig. 1).8 After chiral separation, the (R)-configuration at
envisioned that the 1,2-addition of alkyl metal reagents to suit-
the quaternary stereogenic center was found to be essential
able ketimines (III) would allow a quick structure activity
for the biological activity, since it distributes the biaryl amide
relationship (SAR) study at the quaternary stereocenter. Although
decoration towards S1 and S3 pockets.9,10
there are several methods for the preparation of constrained
As an extension of this work, we became interested in the
acyclic amino acids,12,13 our goal was to develop a general
preparation of β-aryl-β-alkyl aminoalcohols (II, Scheme 1) that
methodology for the direct preparation of suitably protected
could give rise to densely functionalized amidines (I). In order
enantiopure aminoalcohols. At the beginning of this project
there were some criteria that, for the sake of practicality, were
aJanssen Research and Development, Neuroscience Medicinal
Chemistry Department, E-45007 Toledo, Spain.
considered highly desirable. These included the possibility of
carrying out the chemistry in large scale without rigorous exclu-
sion of air or moisture, the use of commercially available
reagents and the avoidance of any tedious separation of enantio-
meric and/or diastereomeric mixtures of products. Herein we
report an experimentally simple protocol for the synthesis of
tertiary carbinamines that proceeds with excellent stereocontrol.
We have applied this methodology to the synthesis of 1,4-oxazine-
amines that inhibit β-secretase in the submicromolar range, as
shown in both the enzymatic and cellular assays.14,15
E-mail: odelgad1@its.jnj.com; Fax: +34 925245771
bLaboratorio de Moléculas Orgánicas, Centro de Investigación Príncipe
Felipe, E-46012 Valencia, Spain
cDepartamento de Química Orgánica, Universidad de Valencia,
E-46100 Burjassot, Spain. E-mail: santos.fustero@uv.es;
Faxl: +34 963544939
†Electronic supplementary information (ESI) available: General experi-
mental procedures, BACE1 assays, stereochemical determination of 7
1
(SFC and VCD analysis) and copies of H and 13C NMR spectra for all
new compounds. See DOI: 10.1039/c2ob25845e
6758 | Org. Biomol. Chem., 2012, 10, 6758–6766
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from which no product could be isolated. The presence of an
electron donating group in the phenyl ring does not have a
noticeable effect on the reactivity of the corresponding imine, as
1,2-addition product 4h can be obtained in good yield (Table 1,
entry 10).22 The stereochemical outcome was in agreement with
previously observed additions to N-sulfinyl ketimines, in which
the incoming nucleophile coordinates the sulfinyl imine oxygen
in a six-membered transition state (Fig. 2).
The 1,2-addition product 4b proved to be an orthogonally pro-
tected building block. Whereas treatment with hydrochloric acid
in methanol gave free amine 6 in good yield (73%), alcohol 5
could be smoothly revealed upon treatment with TBAF in THF.
Both protecting groups could be also simultaneously removed
upon treatment with 37% aqueous hydrochloric acid in dioxane
at reflux temperature. The enantiomeric purity of (R)-amino-
alcohol 7 (97% ee) was determined by chiral supercritical fluid
chromatography (SFC),23 and the absolute configuration was
confirmed by vibrational circular dichroism analysis (VCD). To
expand the versatility of the process, the transformation into the
corresponding Boc-protected amino acid derivative 9 was also
demonstrated (Scheme 2). This procedure constitutes then a new
approach for the synthesis of acyclic quaternary α-amino
acids.12,13
The usefulness of this methodology was demonstrated by the
synthesis of a nanomolar BACE1 inhibitor (15) from our
recently reported BACE1 chemical series.14 Previously, the prep-
aration of these analogues series relied on a racemic synthesis
with later chiral SFC for the isolation of enantiomerically pure
intermediates and final products. As shown in Scheme 3,
(R)-aminoalcohol 7 was treated with 2-chloroacetyl chloride at
−78 °C to give the corresponding chloroamide intermediate
which after addition of KOtBu and warming to −10 °C, gave
morpholinone 10 in 87% yield. The amide functionality was
smoothly transformed into amidine 12 via the corresponding
thioamide 11. A Buchwald-type coupling using benzophenone
imine as ammonia synthetic equivalent yielded protected
amidine 13 in 82% yield. Finally, hydrolysis of the imine to give
14, and subsequent coupling with 5-chloropyridine-2-carboxylic
acid provided the enantiomerically pure target compound (R)-15
with moderate yield (70%). Interestingly, the protection of the
sensitive amidine functionality could be avoided by using N,N-
dimethylaniline as base in the final amide coupling.24 Compound
15 showed 130 and 6.9 nM activity in the enzymatic and cellular
hAβTOT assays respectively.25 This result demonstrates that
the presence of a carbonyl in the amidine containing ring is
not required for in vitro potency.26 Moreover, there are no
difficulties with cell permeation as this and other compounds of
the 1,4-oxazineamines series14 show good cellular activity.
Scheme 1 Retrosynthetic analysis.
Results and discussion
The 1,2-addition of nucleophiles to N-tert-butanesulfinyl keti-
mines is one of the most popular approaches for the asymmetric
preparation of α,α-dibranched amines.16 A clear limitation of
this method is that the level of stereoselectivity is affected by the
Z/E geometry of the imine which, in turn, is dependent on the
relative size of the substituents. Prompted by the work of
Avenoza and Peregrina,17 2-hydroxyacetophenone derivatives
were selected as precursors of imines that exist predominantly in
the (Z)-configuration. We also included a m-bromoaryl ring in
our optimization studies, since it was essential to have an
activated site for the late stage Pd-catalyzed derivatization of the
products.
As shown in Table 1, 2-hydroxy-1-(3-bromophenyl)-
ethanone18 was initially protected as the corresponding t-butyl-
dimethylsilyl (TBS) ether. Condensation of 2a with (S)-
(−)-2-methyl-2-propanesulfinamide in refluxing toluene, using
titanium(IV) isopropoxide as dehydrating agent, gave tert-butyl-
sulfinimine 3a as a 16 : 1 ratio of Z/E isomers. It had been pre-
viously described that organolithium additions to N-sulfinyl
ketimines require the preactivation of the electrophilic partner
with a Lewis acid (AlMe3) in a non-coordinating solvent
(toluene) at low temperature.19 Under these conditions, the
addition of methyllithium to TBS protected ketimine 3a afforded
the tertiary carbinamine 4a with high stereoselectivity (95 : 5)
but in low yield (29%) (Table 1, entry 1). It was reasoned that
the well established α-deprotonation of the N-sulfinyl ketimine
was responsible for the low isolated yield,19 and that the intro-
duction of a bulkier protecting group could prevent this side
reaction. A considerable increase in yield was observed when
tert-butyldiphenylsilyloxy (OTBDPS) ketimine 3b, which was
obtained as a 13 : 1 Z/E isomers ratio, was subjected to identical
reaction conditions (59% yield, Table 1, entry 2). In order to
increase the practicality of the process, our next goal was to omit
Lewis acid activation in the process. While this was not possible
with organolithium reagents (Table 1, entry 3), treatment of
imine 3b with methylmagnesium bromide at 0 °C in CH2Cl2 as
solvent20 gave the desired product 4b in 92% yield as a single
diastereoisomer.21
Conclusions
We have described an expeditious synthesis of enantiomerically
pure β,β-dibranched aminoalcohols making use of Ellman’s
sulfinyl chemistry. The efficiency of the process, both in terms of
yield and stereocontrol is combined with a high degree of experi-
mental simplicity. Noteworthy is the fact that the nucleophiles
are simple commercially available Grignard reagents and that the
chemistry is amenable to being carried out on a multigram scale.
The scope and generality of Grignard additions to 3b in
dichloromethane was then examined. While increasing the size
of the nucleophile resulted in slightly lower yields, the levels of
diastereocontrol were excellent in all cases, as determined by
1H NMR and LC-MS (Table 1, entries 5–7). When PhMgBr was
used (Table 1, entry 8) a complex reaction mixture was obtained
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Table 1 Optimization and substrate scope of the 1,2-addition to sulfinyl imines 3
Entry
1
Imine
Product
Nu-M/additive
MeLi/AlMe3
Solvent
Toluene
Yielda (%)
d.r.b
3a (R = Me, X = m-Br)
29
59
0
95 : 5
2
3
4
5
3b (R = Ph, X = m-Br)
3b (R = Ph, X = m-Br)
3b (R = Ph, X = m-Br)
3b (R = Ph, X = m-Br)
MeLi/AlMe3
Toluene
Toluene
CH2Cl2
CH2Cl2
>97 : 3
MeLi
—
MeMgBr
c-PrMgBr
92
69
>97 : 3
>97 : 3
6
7
8
9
3b (R = Ph, X = m-Br)
3b (R = Ph, X = m-Br)
3b (R = Ph, X = m-Br)
3c (R = Ph, X = H)
EtMgBr
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
75
75
0
>97 : 3
>97 : 3
—
H2CvCHMgBr
PhMgBr
MeMgBr
78
>97 : 3
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Table 1 (Contd.)
Entry
10
Imine
3d (R = Ph, X = p-MeO)
Product
Nu-M/additive
MeMgBr
Solvent
CH2Cl2
Yielda (%)
62
d.r.b
>97 : 3
a Isolated yields. b Determined by 1H NMR.
7.30–7.39 (m, 6H), 7.58–7.71 (m, 6H), 7.93 (t, J = 1.6 Hz, 1H).
13C-NMR (CDCl3, 75.5 MHz) δ 19.3, 26.7, 67.7, 122.8, 126.4,
127.8, 129.9, 130.1, 131.1, 132.7, 135.6, 136.0, 136.7, 195.7.
HRMS (FAB) calcd for C24H25O2BrSiNa [M + Na+]: 475.0699,
found: 475.0689.
General procedure for the synthesis of ketimines 3
(S)-(−)-2-Methyl-2-propanesulfinamide (1.4 eq.) was added to
a stirred solution of ketone 2 (1.0 eq.) and titanium tetraiso-
propoxide (2.5 eq.) in heptane (6 ml mmol−1) at room tempera-
ture under nitrogen. The mixture was heated at 90 °C for
2.5 hours and then allowed to reach room temperature. The
mixture was poured into an equal volume of brine while rapidly
stirring. The resulting suspension was filtered through a plug of
Celite, and the filter cake was washed with EtOAc. The layers
were separated and the organic phase was washed with brine,
dried, filtered and concentrated in vacuo. The residue was
purified by flash chromatography (silica gel; EtOAc in hexane
gradient) to yield imine 3.
Fig. 2 Proposed transition state for the 1,2-addition of Grignard
reagents to sulfinyl imines 3.
Efforts directed towards the preparation of additional analogues
of protease inhibitors bearing this moiety are currently under
way in our laboratories and will be reported in due course.
(S,Z)-N-(1-(3-Bromophenyl)-2-(tert-butyldiphenylsilyloxy)-
ethylidene)-2-methylpropane-2-sulfinamide (3b). The title com-
pound was obtained according to the general procedure
described above starting from ketone 2b (1.20 g, 2.64 mmol).
Purification by flash chromatography (silica gel; EtOAc in
hexane gradient from 0/100 to 10/90) gave imine 3b (0.87 g,
60%) as a bright yellow oil. 1H-NMR (CDCl3, 300 MHz) δ 1.00
(s, 9H), 1.24 (s, 9H), 5.03 (br d, J = 12.7 Hz, 1H), 5.32 (br d,
J = 12.7 Hz, 1H), 7.25 (t, J = 7.9 Hz, 1H), 7.36–7.49 (m, 6H),
7.53–7.66 (m, 6H), 7.87 (br s, 1H). 13C-NMR (CDCl3,
75.5 MHz) δ 19.1, 22.6, 26.6, 58.0, 61.3, 122.1, 127.0, 127.5,
127.8 (2C), 129.5, 129.9, 131.5, 132.4, 133.6, 134.7, 135.5
(2C), 138.8, 176.1. HRMS (FAB) calcd for C28H35NO2SSiBr
[M + H+]: 556.1336, found: 556.1348.
Experimental section
1-(3-Bromophenyl)-2-(tert-butyldiphenylsilyloxy)ethanone (2b)
tert-Butyl(chloro) diphenylsilane (1.42 ml, 5.50 mmol) was
added dropwise to a stirred solution of 2-hydroxy-1-(3-bromo-
phenyl)ethanone18 (1.08 g, 5.02 mmol) and imidazole (0.37 g,
5.50 mmol) in CH2Cl2 (50 ml) at room temperature under nitro-
gen. Then DMAP (40 mg, 0.32 mmol) was added and the result-
ing mixture was stirred at room temperature for 90 minutes. The
mixture was treated with water and extracted with CH2Cl2. The
organic layer was separated, dried (Na2SO4) and the solvents
evaporated in vacuo. The residue was purified by flash chromato-
graphy (silica gel; EtOAc in Hexane 0/100 to 20/80) to yield
(S,Z)-N-(2-(tert-Butyldiphenylsilyloxy)-1-(4-methoxyphenyl)-
ethylidene)-2-methylpropane-2-sulfinamide (3d). The title com-
pound was obtained according to the general procedure
1
ketone 2b as a colorless oil (2.4 g, 100%). H-NMR (CDCl3,
300 MHz) δ 1.05 (s, 9H), 4.78 (s, 2H), 7.23 (t, J = 7.9 Hz, 1H),
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Scheme 2 Synthesis of aminoester 9.
Scheme 3 Synthesis of BACE1 inhibitor 15.
described above starting from ketone 2d27 (136 mg, 0.26 mmol).
General procedure for the synthesis of sulfinamides 4
Purification by flash chromatography (silica gel; EtOAc in
hexane gradient from 0/100 to 10/90) gave imine 3d (81 mg,
62%) as a bright yellow oil. [α]2D5 = +7.8 (c 1.0, CHCl3).
1H-NMR (CDCl3, 300 MHz) δ 1.00 (s, 9H), 1.24 (s, 9H), 3.85
(s, 3H), 4.97 (br s, 1H), 5.24 (br s, 1H), 6.85–6.90 (m, 2H),
7.34–7.46 (m, 6H), 7.62–7.82 (m, 6H). 13C-NMR (CDCl3,
75.5 MHz) δ 19.2, 22.5, 26.7, 55.3, 57.2, 61.3, 113.4, 127.7,
127.8, 129.4, 129.9 (2C), 130.5 (2C), 132.7 (2C), 135.6 (2C),
162.1. HRMS (FAB) calcd for C29H38NO3SSi [M + H+]:
508.2336, found: 508.2336.
A solution of imine 3 (1.0 eq.) in CH2Cl2 (6 ml mmol−1) was
added dropwise to a stirred solution of the corresponding
Grignard reagent (3 M in Et2O or 1 M in THF, 5.0 eq.) in
CH2Cl2 (6 ml mmol−1) at 0 °C under nitrogen. The reaction
mixture was stirred at room temperature for 20 minutes and then
quenched by the addition of 0.5 N HCl. The layers were
separated and the aqueous phase was extracted with CH2Cl2.
The combined organic extracts were dried (Na2SO4), filtered
and concentrated in vacuo. The residue was purified by flash
6762 | Org. Biomol. Chem., 2012, 10, 6758–6766
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chromatography (silica gel; EtOAc in hexane gradient) to afford
compound 4.
130.2, 130.6, 132.5, 132.9, 135.6, 135.7, 144.4. HRMS (FAB)
calcd for C30H41NO2BrSSi [M + H+]: 586.1805, found:
586.1808.
(S)-N-((R)-2-(3-Bromophenyl)-1-(tert-butyldiphenylsilyloxy)-
propan-2-yl)-2-methylpropane-2-sulfinamide (4b). The title
compound was obtained according to the general procedure
described above starting from imine 3b (0.45 g, 0.81 mmol) and
methylmagnesium bromide (3 M in Et2O, 1.47 ml, 4.42 mmol).
Flash chromatography (silica gel; EtOAc in hexane gradient
from 5/95 to 35/65) gave 4b (0.425 g, 92%) as a white solid. Mp
131.2 °C. [α]2D5 = +3.8 (c 1.0, CHCl3). 1H-NMR (CDCl3,
300 MHz) δ 0.98 (s, 9H), 1.26 (s, 9H), 1.60 (s, 3H), 3.76 (d, J =
9.7 Hz, 1H), 3.81 (d, J = 9.7 Hz, 1H), 4.33 (s, 1H), 7.22 (t, J =
7.9 Hz, 1H), 7.29–7.44 (m, 9H), 7.51–7.59 (m, 3H), 7.62
(t, J = 1.8 Hz, 1H). 13C-NMR (CDCl3, 75.5 MHz) δ 19.1, 22.6,
24.9, 26.6, 56.1, 61.7, 72.3, 122.3, 126.0, 127.7 (2C), 129.6,
129.8 (2C), 130.1, 130.2, 132.3, 132.7, 135.3 (2C), 146.7.
HRMS (FAB) calcd for C25H31NOSiBr [M − (t-BuSO) + H+]:
468.1353, found: 468.1345.
(S)-N-((R)-2-(3-Bromophenyl)-1-(tert-butyldiphenylsilyloxy)-
but-3-en-2-yl)-2-methylpropane-2-sulfinamide (4e). The title
compound was obtained according to the general procedure
described above starting from imine 3b (100 mg, 0.18 mmol)
and vinylmagnesium bromide (1
M in THF, 0.54 ml,
0.54 mmol). Purification by flash chromatography (silica gel;
EtOAc in hexane gradient from 5/95 to 50/50) gave 4e (78 mg,
1
75%) as a colorless oil. [α]2D5 = +23.3 (c 1.0, CHCl3). H-NMR
(CDCl3, 300 MHz) δ 0.98 (s, 9H), 1.26 (s, 9H), 3.95 (d, J =
9.6 Hz, 1H), 4.13 (d, J = 9.6 Hz, 1H), 4.42 (s, 1H), 5.24 (dd, J =
17.4, 0.6 Hz, 1H), 5.36 (dd, J = 10.8, 0.6 Hz, 1H), 5.94 (dd,
J = 17.4, 10.8 Hz, 1H), 7.21 (t, J = 7.9 Hz, 1H), 7.33–7.51 (m,
10H), 7.57–7.61 (m, 3H). 13C-NMR (CDCl3, 75.5 MHz) δ 19.5,
23.1, 27.0, 56.7, 66.5, 70.2, 117.8, 122.6, 127.5, 128.1 (2C),
129.9, 130.2 (2C), 131.0, 131.9, 132.7, 133.1, 135.9, 136.0,
140.2, 143.1. HRMS (FAB) calcd for C30H38NO2BrSSi
[M + H+]: 584.1649, found: 584.1639.
(S)-N-((R)-1-(3-Bromophenyl)-2-(tert-butyldiphenylsilyloxy)-1-
cyclopropylethyl)-2-methylpropane-2-sulfinamide (4c). Bromo-
cyclopropane (0.63 ml, 7.90 mmol) was added to a suspen-
sion of magnesium turnings (208 mg, 7.90 mmol) in Et2O
(4 ml) at room temperature. The resulting mixture was refluxed
for 30 minutes and allowed to reach room temperature. A solu-
tion of imine 3b (0.88 g, 1.58 mmol) in CH2Cl2 (10 ml) was
added dropwise to the freshly prepared solution of cyclopropyl-
magnesium bromide at 0 °C under nitrogen. The reaction
mixture was stirred at room temperature for 10 minutes and then
quenched by the addition of 0.5 N HCl (5 ml). The layers were
separated and the aqueous phase was extracted with CH2Cl2.
The combined organic extracts were dried (Na2SO4), filtered and
concentrated in vacuo. The residue was purified by flash
chromatography (silica gel; EtOAc in hexane gradient from 5/95
(S)-N-((R)-1-(tert-Butyldiphenylsilyloxy)-2-phenylpropan-2-yl)-
2-methylpropane-2-sulfinamide (4g). The title compound was
obtained according to the general procedure described above
starting from imine 3c17 (96 mg, 0.21 mmol) and methylmagne-
sium bromide (3 M in Et2O, 0.36 ml, 1.08 mmol). Purification
by flash chromatography (silica gel; EtOAc in hexane gradient
from 5/95 to 40/60) gave 4g (81 mg, 78%) as a colorless oil.
[α]2D5 = +0.3 (c 1.0, CHCl3). 1H-NMR (CDCl3, 300 MHz) δ 0.97
(s, 9H), 1.25 (s, 9H), 1.67 (3H), 3.76 (d, J = 9.6 Hz, 1H), 3.86
(d, J = 9.6 Hz, 1H), 4.31 (s, 3H), 7.26–7.40 (m, 11H), 7.48–7.56
(m, 4H). 13C-NMR (CDCl3, 75.5 MHz) δ 19.2, 22.7, 25.0, 26.7,
56.0, 61.9, 72.5, 127.0, 127.2, 127.6, 127.7, 128.1, 129.7 (2C),
132.6, 133.0, 135.6 (2C), 143.8. HRMS (FAB) calcd for
C29H40NO2SSi [M + H+]: 494.2544, found: 494.2547.
to 40/60) to yield 4c (0.65 g, 69%) as a colorless oil. [α]D25
=
1
−2.4 (c 1.0, CHCl3). H-NMR (CDCl3, 300 MHz) δ 0.15–0.23
(m, 1H), 0.32–0.40 (m, 1H), 0.42–0.51 (m, 1H), 0.53–0.64 (m,
1H), 0.94 (s, 9H), 1.10–1.21 (m, 1H), 1.25 (s, 9H), 3.77 (d, J =
9.8 Hz, 1H), 3.99 (d, J = 9.8 Hz, 1H), 4.31 (s, 1H), 7.20 (t, J =
8.3 Hz, 1H), 7.32–7.59 (m, 9H), 7.58–7.64 (m, 4H). 13C-NMR
(CDCl3, 75.5 MHz) δ 1.6, 2.2, 17.8, 19.0, 22.7, 26.6, 56.0, 64.9,
70.3, 121.8, 127.6, 127.7 (2C), 129.3, 129.8 (2C), 130.1, 131.7,
132.2, 132.7, 135.4, 135.6, 143.5. HRMS (FAB) calcd for
C31H41NO2BrSSi [M + H+]: 598.1805, found: 598.1802.
(S)-N-((R)-1-(tert-Butyldiphenylsilyloxy)-2-(4-methoxyphenyl)-
propan-2-yl)-2-methylpropane-2-sulfinamide (4h). The title
compound was obtained according to the general procedure
described above starting from imine 3d (40 mg, 0.078 mmol)
and methylmagnesium bromide (3 M in Et2O, 0.131 ml,
0.39 mmol). Purification by flash chromatography (silica gel;
EtOAc in hexane gradient from 5/95 to 40/60) gave 4h (31 mg,
1
75%) as a colorless oil. [α]2D5 = +8.1 (c 1.0, CHCl3). H-NMR
(CDCl3, 300 MHz) δ 0.99 (s, 9H), 1.24 (s, 9H), 1.62 (s, 3H),
3.76 (d, J = 9.6 Hz, 1H), 3.81 (s, 3H), 3.86 (d, J = 9.6 Hz, 1H),
4.27 (s, 1H), 6.86 (d, J = 8.9 Hz, 2H), 7.31–7.44 (m, 10H),
7.53–7.58 (m, 2H). 13C-NMR (CDCl3, 75.5 MHz) δ 18.9, 22.5,
25.0, 26.5, 55.0, 55.7, 61.1, 72.2, 113.1, 127.4, 127.5, 128.0,
129.5 (2C), 132.5, 132.8, 135.3, 135.4, 135.5, 158.5. HRMS
(FAB) calcd for C30H42NO3SSi [M + H+]: 524.2649, found:
524.2672.
(S)-N-((R)-2-(3-Bromophenyl)-1-(tert-butyldiphenylsilyloxy)-
butan-2-yl)-2-methylpropane-2-sulfinamide (4d). The title com-
pound was obtained according to the general procedure
described above starting from imine 3b (100 mg, 0.18 mmol)
and ethylmagnesium bromide (1
M in THF, 0.89 ml,
0.89 mmol). Purification by flash chromatography (silica gel;
EtOAc in hexane gradient from 5/95 to 50/50) gave 4d (65 mg,
65%) as a colorless oil. [α]2D5 = +22.9 (c 0.87, CHCl3). 1H-NMR
(CDCl3, 300 MHz) δ 0.63 (t, J = 7.3 Hz, 3H), 0.94 (s, 9H), 1.21
(s, 9H), 1.88 (dq, J = 14.7, 7.3 Hz, 1H), 2.00 (dq, J = 14.6,
7.3 Hz, 1H), 3.90 (AB q, J = 9.8 Hz, 2H), 4.10 (s, 1H), 7.12 (t,
J = 7.9 Hz, 1H), 7.28–7.40 (m, 8H), 7.43–7.54 (m, 5H).
13C-NMR (CDCl3, 75.5 MHz) δ 7.8, 19.2, 22.8, 26.8, 30.2,
56.4, 64.8, 68.5, 122.4, 126.1, 127.7 (2C), 129.6, 129.8 (2C),
(S)-N-((R)-2-(3-Bromophenyl)-1-hydroxypropan-2-yl)-2-methyl-
propane-2-sulfinamide (5). TBAF (1 M in THF, 0.73 ml,
0.73 mmol) was added dropwise to a stirred solution of sulfinyl
amine 4b (320 mg, 0.56 mmol) in THF (5 ml) at room tempera-
ture. The mixture was stirred for 3 hours at room temperature.
The mixture was treated with water and extracted with EtOAc.
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1
The organic layer was separated, dried (Na2SO4), filtered and
concentrated in vacuo. The residue was purified by flash
chromatography (silica gel; MeOH in CH2Cl2 0/100 to 10/90).
The desired fractions were collected and concentrated in vacuo
to yield alcohol 5 (164 mg, 88%) as a white solid. Mp 151.1 °C.
CHCl3). H-NMR (CDCl3, 300 MHz) δ 1.40 (br s, 9H), 1.58 (s,
3H), 3.53–3.77 (m, 3H), 5.30 (br s, 1H), 7.21 (t, J = 7.8 Hz,
1H), 7.28 (t, J = 7.8 Hz, 1H), 7.38 (ddd, J = 7.8, 1.8, 1.2 Hz,
1H), 7.55 (t, J = 1.8 Hz, 1H), 7. 13C-NMR (CDCl3, 75.5 MHz)
δ 24.5, 28.2, 59.6, 70.8, 80.2, 122.7, 124.3, 128.9, 130.0, 130.1,
146.0, 155.8. HRMS (FAB) calcd for C14H20NO3BrNa
[M + Na+]: 352.0519, found: 352.0509.
1
[α]2D5 = +45.1 (c 1.0, CHCl3). H-NMR (CDCl3, 300 MHz) δ
1.29 (s, 9H), 1.49 (s, 3H), 3.72–3.94 (m, 3H), 4.21 (d, J = 10.1
Hz, 1H), 7.22 (t, J = 7.9 Hz, 1H), 7.32–7.36 (m, 1H), 7.42 (ddd,
J = 7.9, 1.9, 1.1 Hz, 1H), 7.59 (t, J = 1.8 Hz, 1H). 13C-NMR
(CDCl3, 75.5 MHz) δ 22.6, 29.3, 56.5, 61.8, 68.1, 122.6, 124.9,
129.9, 130.0, 130.4, 145.8. HRMS (FAB) calcd for
C13H21NO2SBr [M + H+]: 334.0471, found: 334.0484.
(R)-Methyl 2-(3-bromophenyl)-2-(tert-butoxycarbonylamino)-
propanoate (9). A solution of NaClO2 (80% purity, 27 mg,
0.24 mmol) in sodium phosphate buffer (pH = 6.7) was added
dropwise to a stirred mixture of alcohol 8 (40 mg, 0.121 mmol)
and TEMPO (1.9 mg, 0.012 mmol) in acetonitrile (1 ml) at
room temperature. The reaction temperature was risen to 35 °C
and then a solution of NaOCl (14% active Cl, 5 μL) in water
(1 ml) was added dropwise over a period of 1 hour. The reaction
mixture was stirred at 35 °C for 18 hours. After cooling the reac-
tion mixture to 25 °C, water was added and the pH was adjusted
to 8.0 by addition of 2 N NaOH. The reaction mixture was then
poured into ice-cold sodium sulfite solution. After stirring for
30 minutes at room temperature Et2O was added and the organic
layer was separated and discarded. More Et2O was added and
the mixture was acidified with 2 N HCl to pH 3–4. The organic
layer was separated and the aqueous layer was extracted with
EtOAc. The combined organic extracts were washed with brine
and then concentrated in vacuo to yield the crude carboxylic
acid as a white solid. This material was dissolved in a mixture of
toluene (2 ml) and MeOH (0.2 ml) at room temperature. Then
TMS–diazomethane (2 M in hexane, 0.104 ml, 0.21 mmol) was
added and the mixture was stirred at room temperature for
30 minutes. The excess diazomethane was quenched by the
addition of few droplets of AcOH and the solvents were evapo-
rated in vacuo. The residue was purified by flash chromatography
(silica gel; EtOAc in hexane 10/90 to 40/60). The desired frac-
tions were collected and concentrated in vacuo to yield methyl
ester 9 (32 mg, 86%) as a colorless oil. [α]2D5 = −42.9 (c 1.07,
(R)-2-(3-Bromophenyl)-1-(tert-butyldiphenylsilyloxy)propan-
2-amine (6). HCl (2 M in Et2O, 1.0 ml, 2.0 mmol) was added
dropwise to a stirred solution of sulfinyl amine 4b (160 mg,
0.28 mmol) in MeOH (2 ml) at room temperature. The mixture
was stirred for 2 hours at room temperature. The mixture was
treated with sat. aq. NaHCO3 and extracted with CH2Cl2. The
organic layer was separated, dried (Na2SO4), filtered and concen-
trated in vacuo. The residue was purified by flash chromato-
graphy (silica gel; MeOH in CH2Cl2 0/100 to 5/95). The desired
fractions were collected and concentrated in vacuo to yield
amine 6 (95 mg, 73%) as a colorless oil. [α]2D5 = +6.6 (c 1.1,
CHCl3). 1H-NMR (CDCl3, 300 MHz) δ 1.02 (s, 9H), 1.45
(s, 3H), 1.79 (s, 2H), 3.60–3.68 (m, 2H), 7.18 (t, J = 7.6 Hz,
1H), 7.31–7.52 (m, 10H), 7.56–7.62 (m, 2H), 7.66 (t, J =
1.8 Hz, 1H). 13C-NMR (CDCl3, 75.5 MHz) δ 19.2, 26.8, 27.0,
56.4, 73.3, 122.4, 124.5, 127.7, 129.3, 129.5, 129.7, 133.0,
133.1, 135.5, 149.2. HRMS (FAB) calcd for C25H31NOSiBr
[M + H+]: 468.1358, found: 468.1374.
(R)-2-Amino-2-(3-bromophenyl)propan-1-ol (7). HCl (37% in
H2O, 10 ml) was added dropwise to a stirred solution of sulfinyl
amine 4b (0.96 g, 1.67 mmol) in 1,4-dioxane (10 ml) at room
temperature. The mixture was refluxed for 3 hours and then
allowed to reach room temperature. The mixture was basified
with sat. aq. Na2CO3 and extracted with EtOAc. The organic
layer was separated, dried (Na2SO4), filtered and concentrated
in vacuo. The residue was purified by flash chromatography
(silica gel; 7 N NH3/MeOH in CH2Cl2 0/100 to 10/90). The
desired fractions were collected and concentrated in vacuo to
1
CHCl3). H-NMR (CDCl3, 300 MHz) δ 1.36 (br s, 3H), 1.97 (s,
3H), 3.70 (s, 3H), 5.90 (br s, 1H), 7.21 (t, J = 7.9 Hz, 1H),
7.36–7.43 (m, 2H), 7.58 (t, J = 1.8 Hz, 1H). 13C-NMR (CDCl3,
75.5 MHz) δ 23.1, 28.2, 53.2, 61.4, 80.1, 122.6, 124.6, 129.2,
130.0, 130.8, 143.3, 153.9, 173.1. HRMS (FAB) calcd for
C15H20NO4BrNa [M + Na+]: 380.0468, found: 380.0477.
yield amino alcohol 7 (340 mg, 88%) as a glassy solid. [α]D25
=
−9.7 (c 0.64, MeOH). 1H-NMR (CDCl3, 300 MHz) δ 1.40
(s, 3H), 2.47 (s, 3H), 3.55 (AB q, J = 10.8 Hz, 2H), 7.20 (t, J =
7.9 Hz, 1H), 7.31–7.40 (m, 2H), 7.59 (t, J = 1.8 Hz, 1H).
13C-NMR (CDCl3, 75.5 MHz) δ 26.9, 56.4, 71.3, 122.7, 124.1,
128.8, 129.8, 129.9, 148.6. HRMS (FAB) calcd for C9H13NOBr
[M + H+]: 230.0175, found: 230.0169.
(R)-5-(3-Bromophenyl)-5-methylmorpholin-3-one (10). 2-Chloro-
acetylchloride (0.658 ml, 8.26 mmol) was added dropwise to a
stirred solution of amino alcohol 7 (1.90 g, 8.26 mmol) and
DIPEA (1.71 ml, 9.90 mmol) in THF (70 ml) at −78 °C. The
mixture was stirred for 20 minutes at −78 °C. Then potassium
tert-butoxide (2.32 g, 20.6 mmol) was added and the mixture
was allowed to reach −10 °C over 60 minutes. The mixture was
diluted with saturated NH4Cl and extracted with CH2Cl2. The
organic layer was separated, dried (Na2SO4), filtered and the
solvents evaporated in vacuo. The crude product was purified
by flash chromatography (silica gel; MeOH in CH2Cl2 0/100 to
3/97). The desired fractions were collected and the solvents
evaporated in vacuo to yield lactam 10 (1.93 g, 87%) as a white
solid. Mp 127.8 °C. [α]2D5 = −66.5 (c 1.0, CHCl3). 1H-NMR
(CDCl3, 300 MHz) δ 1.68 (s, 3H), 3.73 (d, J = 11.7 Hz, 1H),
3.85 (d, J = 11.7 Hz, 1H), 4.24 (s, 2H), 6.85 (br s, 1H),
(R)-tert-Butyl 2-(3-bromophenyl)-1-hydroxypropan-2-yl car-
bamate (8). Di-tert-butyl dicarbonate (137 mg, 0.63 mmol) was
added portion wise to a stirred mixture of 7 (48 mg, 0.21 mmol)
in THF (4 ml) and sat. aq. NaHCO3 (4 ml) at 0 °C. The mixture
was stirred at room temperature for 16 hours. The mixture was
diluted with water and extracted with CH2Cl2. The organic
layer was dried (Na2SO4), filtered and the solvents evaporated
in vacuo. The crude product was purified by flash chromato-
graphy (silica gel; EtOAc in hexane 0/100 to 20/80) to afford
alcohol 8 (53 mg, 80%) as a colorless oil. [α]2D5 = −6.1 (c 1.0,
6764 | Org. Biomol. Chem., 2012, 10, 6758–6766
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7.26–7.37 (m, 2H), 7.47 (dt, J = 7.7, 1.5 Hz, 1H), 7.56 (t, J =
1.9 Hz, 1H). 13C-NMR (CDCl3, 75.5 MHz) δ 25.8, 57.7, 67.4,
74.3, 123.0, 124.1, 128.7, 130.3, 130.8, 145.3, 169.2. HRMS
(FAB) calcd for C11H12NO2Br [M + H+]: 270.0124, found:
270.0116.
7.21–7.27 (m, 3H), 7.38–7.49 (m, 3H), 7.72–7.77 (m, 2H).
13C-NMR (CDCl3, 100.6 MHz) δ 26.4, 56.0, 62.7, 73.5, 118.9,
119.7, 120.8, 127.9, 128.2, 128.3, 128.4, 129.3, 129.6, 130.6,
136.3, 139.7, 146.3, 150.9, 155.9, 168.3. HRMS (FAB) calcd
for C24H24N3O [M + H+]: 370.1919, found: 370.1910.
(R)-5-(3-Bromophenyl)-5-methylmorpholine-3-thione (11).
Phosphorus pentasulfide (3.29 g, 14.8 mmol) was added to a sol-
ution of amide 10 (5.00 g, 18.5 mmol) in THF (192 ml) at room
temperature. The mixture was stirred at 50 °C for 60 minutes and
then allowed to reach room temperature. The mixture was
filtered over cotton and evaporated in vacuo. The crude product
was purified by flash column chromatography (silica gel;
CH2Cl2). The desired fractions were collected and evaporated
in vacuo to yield thioamide 11 (4.70 g, 89%) as a sticky foam.
(R)-5-(3-Aminophenyl)-5-methyl-5,6-dihydro-2H-1,4-oxazin-3-
amine (14). The mixture of amidine 12 (1.00 g, 3.71 mmol),
Pd2(dba)3 (340 mg, 0.17 mmol), 2,2′-bis(diphenylphosphino)-
1,1′-binaphthyl (694 mg, 1.11 mmol) and sodium tert-butoxide
(535 mg, 5.57 mmol) in toluene (30 ml) was purged with nitro-
gen for five minutes before the addition of benzophenone imine
(0.810 ml, 4.83 mmol). The resulting mixture was stirred in a
sealed tube at 70 °C for 18 hours. After cooling, 1 N HCl
(20 ml) was added and the mixture stirred at room temperature
for 1 hour. The mixture was diluted with water and washed with
EtOAc. The aqueous layer was basified with sat. aq. Na2CO3
and extracted with CH2Cl2/EtOH (9/1, 10 times). The combined
organic layers were dried (Na2SO4), filtered and the solvents
concentrated in vacuo. The crude product was purified by flash
column chromatography (silica gel; 7 N NH3 in MeOH in
CH2Cl2 0/100 to 10/90). The desired fractions were collected
and concentrated in vacuo to yield 14 (410 mg, 54%) as a glassy
solid. This material was used in the following reaction without
further purification.
1
[α]2D5 = −137.6 (c 1.0, CHCl3). H-NMR (CDCl3, 300 MHz) δ
1.70 (s, 3H), 3.75 (d, J = 11.8 Hz, 1H), 3.87 (d, J = 11.8 Hz,
1H), 4.57 (s, 2H), 7.26–7.30 (m, 2H), 7.45–7.50 (m, 2H), 8.80
(br s, 1H). 13C-NMR (CDCl3, 75.5 MHz) δ 24.7, 59.2, 73.0,
73.6, 123.2, 124.3, 128.8, 130.5, 131.4, 143.7, 198.8. HRMS
(FAB) calcd for C11H13NOSBr [M + H+]: 285.9896, found:
285.9903.
(R)-5-(3-Bromophenyl)-5-methyl-5,6-dihydro-2H-1,4-oxazin-3-
amine (12). A suspension of thioamide 11 (1.86 g, 6.50 mmol)
in ammonia (32% aqueous, 30 ml) was stirred at 60 °C for
3 hours in a sealed tube. The mixture was cooled to 0 °C and a
7 N solution of ammonia in MeOH (10 ml, 70 mmol) was
added. The resulting mixture was stirred at 60 °C for 3 hours.
The mixture was cooled to room temperature, diluted with water
and extracted with CH2Cl2. The organic layer was separated,
dried (Na2SO4), filtered and the solvents evaporated in vacuo.
The crude product was purified by flash chromatography (silica
gel; MeOH in CH2Cl2 0/100 to 5/95; then (7 N ammonia in
MeOH) in CH2Cl2 5/95). The desired fractions were collected
and concentrated in vacuo to yield amidine 12 (1.45 g, 83%) as
a glassy solid. [α]D25 = −125.8 (c 1.0, CHCl3). 1H-NMR (CDCl3,
300 MHz) δ 1.48 (s, 3H), 3.54 (d, J = 11.3 Hz, 1H), 3.65 (d, J =
11.3 Hz, 1H), 3.97–4.14 (m, 4H), 7.18 (t, J = 7.8 Hz, 1H),
7.28–7.38 (m, 2H), 7.57 (t, J = 1.8 Hz, 1H). 13C-NMR (CDCl3,
75.5 MHz) δ 26.8, 56.0, 62.6, 73.3, 122.5, 124.4, 129.3, 129.6,
129.7, 148.7, 156.2. HRMS (FAB) calcd for C11H14BrN2O
[M + H+]: 269.0284, found: 269.0293.
(R)-N-(3-(5-Amino-3-methyl-3,6-dihydro-2H-1,4-oxazin-3-yl)-
phenyl)-5-chloropicolinamide (15). 5-Chloropyridine-2-carboxy-
lic acid (28 mg, 0.146 mmol) was added to a solution of
amidine 14 (20 mg, 0.097 mmol) in CH2Cl2 (1.5 ml) at room
temperature. Then N,N-dimethylaniline (18.5 μl, 0.146 mmol)
was added and after stirring for 5 minutes at room temperature,
HATU (42 mg, 0.112 mmol) was added. The mixture was stirred
at room temperature for 2.5 hours. The mixture was diluted with
water and sat. Na2CO3 and extracted with CH2Cl2. The organic
layer was separated, dried (Na2SO4), filtered and the solvents
evaporated in vacuo. The crude product was purified by flash
chromatography (silica; (7 N ammonia in MeOH) in CH2Cl2
0/100 to 4/96). The desired fractions were collected and concen-
trated in vacuo. The product was then purified again by flash
chromatography (silica; MeOH in CH2Cl2 0/100 to 4/96). The
desired fractions were collected and concentrated in vacuo yield-
ing 15 (26 mg, 70%) as a sticky white product. [α]2D5 = −88.8
(c 0.68, DMF). 1H-NMR (CDCl3, 500 MHz) δ 1.57 (s, 3H),
3.63 (d, J = 11.3 Hz, 1H), 3.74 (d, J = 11.6 Hz, 1H), 4.08–4.18
(m, 2H), 7.21 (d, J = 7.8 Hz, 1H), 7.37 (t, J = 7.9 Hz, 1H),
7.70–7.80 (m, 2H), 7.89 (dd, J = 8.4, 2.3 Hz, 1H), 8.26 (d, J =
8.4 Hz, 1H), 8.55 (d, J = 2.0 Hz, 1H), 9.85 (br s, 1H). 13C-NMR
(CDCl3, 100.6 MHz) δ 26.9, 56.2, 62.9, 73.5, 117.4, 118.1,
122.0, 123.4, 129.1, 135.3, 137.4, 137.5, 147.0, 147.2, 148.0,
156.5, 161.1. HRMS (FAB) calcd for C17H18N4O2Cl [M + H+]:
345.1118, found: 345.1114.
(R)-5-[3-(Benzhydrylideneamino)phenyl]-5-methyl-2,6-dihydro-
2H-1,4-oxazin-3-amine (13). The mixture of amidine 12
(130 mg, 0.48 mmol), Pd2(dba)3 (44 mg, 0.048 mmol), 2,2′-bis
(diphenylphosphino)-1,1′-binaphthyl (90 mg, 0.145 mmol) and
sodium tert-butoxide (69 mg, 0.72 mmol) in toluene (4 ml) was
purged with nitrogen for five minutes before the addition of
benzophenone imine (0.105 ml, 0.628 mmol). The resulting
mixture was stirred in a sealed tube at 70 °C for 18 hours. After
cooling, the solvents were removed in vacuo. The crude product
was purified by flash chromatography (silica gel; 7 N NH3 in
MeOH in CH2Cl2 0/100 to 6/94). The desired fractions were col-
lected and concentrated in vacuo to yield 13 (146 mg, 82%) as a
yellow oil. [α]2D5 = −16.1 (c 0.51, DMF). 1H-NMR (CDCl3,
400 MHz) δ 1.35 (s, 3H), 3.27 (d, J = 11.3 Hz, 1H), 3.49 (d, J =
11.3 Hz, 1H), 3.94 (d, J = 15.3 Hz, 1H), 4.06 (d, J = 15.5 Hz,
1H), 6.64–6.71 (m, 2H), 6.96–7.02 (m, 1H), 7.08–7.15 (m, 3H),
Acknowledgements
We acknowledge the Spanish Ministerio de Ciencia e Innovación
(CTQ2010-19774) and Generalitat Valenciana (PROMETEO/
2010/061) for their financial support. We also thank Alberto
Fontana for providing accurate mass measurement analysis.
This journal is © The Royal Society of Chemistry 2012
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M. Rogers-Evans, M. Travagli, M. Valacchi, T. Woltering and W. Wostl,
WO Patent, 020 806, 2011.
Notes and references
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24 When using Et3N as base, coupling of the amidine to the carboxylic acid
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25 For biological assays details, see ESI.†
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6766 | Org. Biomol. Chem., 2012, 10, 6758–6766
This journal is © The Royal Society of Chemistry 2012