Stereoselective synthesis of 1,3-amino alcohols by the Pd-catalyzed cyclization of trichloroacetimidates

Article abstract of DOI:10.1021/jo402681z

The synthesis of 4-vinyl-5,6-dihydro-1,3-oxazines, precursors of 1,3-amino alcohols, using the palladium-catalyzed cyclization of trichloroacetimidates is reported. The reaction favors the formation of the 4,6-cis-isomers with up to >20:1 diastereoselecti

Full text of DOI:10.1021/jo402681z

Article
pubs.acs.org/joc
Stereoselective Synthesis of 1,3-Amino Alcohols by the Pd-Catalyzed
Cyclization of Trichloroacetimidates
Yuanzhen Xie, Kai Yu, and Zhenhua Gu*
Department of Chemistry, University of Science and Technology of China, 96 Jinzhai Road, Hefei, Anhui 230026, P. R. China
S
* Supporting Information
ABSTRACT: The synthesis of 4-vinyl-5,6-dihydro-1,3-oxazines, pre-
cursors of 1,3-amino alcohols, using the palladium-catalyzed cyclization
of trichloroacetimidates is reported. The reaction favors the formation
of the 4,6-cis-isomers with up to >20:1 diastereoselectivity. Chemo-
selective hydrolysis of the resulting 5,6-dihydro-1,3-oxazines was also
investigated.
group would constrain the conformation of the transition state
and enable good stereoselectivity.
INTRODUCTION
■
1,3-Amino alcohols are an important class of organic
compounds that not only are widely represented in natural
products and pharmaceuticals but also are useful synthons for
organic syntheses.1,2 The asymmetric construction of β-amino
ketones or aldehydes,3 β-hydroxy imines,4 or 2,3-dihydro-
isoxazoles5 followed by stereoselective reduction is an important
pathway for the synthesis of 1,3-amino alcohols (Scheme 1a).
Transition-metal-catalyzed aliphatic C−H amination with
nitrenes6 and allylic C−H amination reactions are straightfor-
ward and atom-economical methods to access this structural
motif (Scheme 1b).7 Treatment of 2-pentene-1,5-diol with
tosyl isocyanate followed by palladium-catalyzed cyclization
affords protected trans-1,3-amino alcohol derivatives selectively
(Scheme 1c).8 Following the ongoing studies of relay
sequences combining hemiacetalization and intramolecular
allylic amination/oxygenation using rhenium9 or palladium
catalysis,10 Menche and co-workers developed a new method
for the preparation of 1,3-amino alcohol derivatives from
tosylated aldimines in the presence of a palladium catalyst. The
reaction affords four diastereomeric 1,3-oxazines, generally
favoring the 4,6-cis isomers with low to moderate selectivity
(Scheme 1c).11
Creating new chiral centers through substrate control
remains an important strategy in asymmetric synthesis. We
are interested in the development of methods for the synthesis
of 1,3-amino alcohol derivatives from stereodefined homoallylic
alcohols using the Tsuji−Trost reaction.12 These methods
should satisfy the following requirements: (a) the reactions
should use inexpensive, stable, and readily available materials;
(b) the products should be readily cleaved to afford free 1,3-
amino alcohols; and (c) both the hydroxyl and amino func-
tional groups should be easily and selectively modifiable with-
out excessive manipulations of protecting groups. We reasoned
that trichloroacetimidates,13 which have been extensively
studied by the Overman group for the preparation of allylic
amines,14 might be a good candidate for our purposes. We
also anticipated that the steric bulk of the trichloroacetimidate
RESULTS AND DISCUSSION
■
Our initial trials started with trichloroacetimidate 1a, which was
easily prepared in two steps from 1-phenylbut-3-en-1-ol.15 To
our delight, in the presence of 5 mol % Pd(OAc)2, 1a was
converted to 5,6-dihydro-1,3-oxazine 2a in 62% yield with 7.0:1
diastereoselectivity favoring the cis product after 3 days at room
temperature (Table 1, entry 1). The two isomers could be
separated by chromatography on silica gel, and the stereo-
chemistry was assigned by both NMR (J values and NOESY
correlations) and X-ray analysis of cis-2a (see the Supporting
Information).16 With PdCl2 as the catalyst, the reaction
provided a similar isolated yield, but the diastereoselectivity
dropped dramatically (entry 2). It was found that the reaction
was much cleaner with Pd(dba)2 as the catalyst, furnishing 2a in
86% isolated yield (dr 5.7:1) with Et2O as the solvent (entry 3).
Further screening revealed that THF was the optimal solvent,
in which the reaction delivered the desired product in 91% yield
with 7.3:1 diastereoselectivity (entries 4 and 5). The cyclization
reaction gave a slightly increased stereoselectivity at 20 °C
(entry 6). When substituted dibenzylideneacetones with
different electronic properties (e.g., L1 and L2) were used as
the ligands, no significant changes in either the yield or the
stereoselectivity were observed (entries 7 and 8). The
combination of Pd(dba)2 and a phosphite ligand [i.e.,
P(OPh)3] reduced the rate of the reaction, and only 17%
conversion was observed after 3 days at 25 °C (entry 9).17 The
reaction did not proceed at all when Pd(PPh3)4 or iridium(I)
was used as the catalyst (entries 10 and 11).18
It should be noted that the geometry of the CC double
bond had little influence on either the yield or stereoselectivity.
Treatment of (Z)-1a with Pd(dba)2 under identical conditions
gave 2a in 88% overall yield favoring the cis product with a
similar dr value (Scheme 2), indicating that the selectivity is not
Received: December 8, 2013
© XXXX American Chemical Society
A
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Scheme 1. Syntheses of 1,3-Amino Alcohols
dependent on the double-bond geometry in the substrate.
Furthermore, independently subjecting both cis- and trans-2a to
the standard reaction conditions showed that there is no
equilibration between the two diastereomers in the presence of
Pd(0) species.
We subsequently investigated the effect of the leaving group
in this reaction. It was found that both the yield and the
diastereoselectivity are significantly influenced by the properties
of the leaving group (Table 2). With trichloroacetimidate as the
leaving group, the reaction gave a moderate yield and a diaste-
reoselectivity of 2.0:1 (entry 1). No satisfactory diastereo-
selectivities were observed when a carboxy ester (OAc, OPiv)
or chloride was used as the leaving group (entries 2−4).
Furthermore, in the case of methyl carbonate only very low
conversion was observed under the same reaction conditions
(entry 5).
4-substituted benzylic alcohols revealed that good to excellent
yields could be achieved (2b−f), although the p-NO2-
substituted substrate gave a relatively lower diastereoselectivity
(2e). Substrates with a 3-substituted phenyl ring or 2-naphthyl
group could also be smoothly converted to 5,6-dihydro-1,3-
oxazines in good yields and stereoselectivities (2g−k). Notably,
the selectivity of this reaction is significantly impacted by the
steric bulk adjacent to the trichloroacetimidate functionality.
The reaction of 2-substituted phenyl or 1-naphthalene
derivatives furnished the products in excellent yields and
diastereoselectivities of up to >20:1 (2l−n). When the R group
was an aliphatic group, the same steric effect was observed: the
reaction with a hydrocinnamaldehyde-derived substrate
afforded 5,6-dihydro-1,3-oxazines 2o with 2.3:1 diastereoselec-
tivity, while the α-branched substrate furnished product 2p
with >90% diastereomeric purity. A compound derived from
(R)-glyceraldehyde-1,2-acetonide19 was also a suitable sub-
strate, affording cyclization product 2q in 80% yield with mod-
erate diastereoselectivity.
The generality of the reaction was explored under the
optimized conditions, and the results are listed in Table 3.
Examination of a series of trichloroacetimidates derived from
B
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a
Table 1. Optimization of the Reaction Conditions
b
entry
catalyst
Pd(OAc)2
solvent
T (°C)
t (days)
% yield (cis:trans) of 2a
1
2
DCM
DCM
Et2O
PhMe
THF
THF
THF
THF
THF
THF
THF
25
25
25
25
25
20
25
25
25
25
70
3
62 (7.0:1)
65 (3.3:1)
86 (5.7:1)
87 (5.0:1)
91 (7.3:1)
90 (8.5:1)
90 (7.5:1)
86 (7.2:1)
PdCl2
3.5
3
3
Pd(dba)2
Pd(dba)2
Pd(dba)2
Pd(dba)2
Pd(L1)2
4
3
5
2.5
2.5
3.5
3.5
3
6
7
8
Pd(L2)2
d
9
Pd(dba)2/P(OPh)3
Pd(PPh3)4
17 (conv.)
10
11
3
NR
c
[Ir(COD)Cl]2/L3
1
NR
a
b
c
d
The reactions were conducted on a 0.20 mmol scale of 1a. Isolated yields. 2.5 mol % [Ir(COD)Cl]2 and 10 mol % L3 were used. 10 mol %
P(OPh)3 was used; conv. = conversion.
The hydrolysis of cis-2a with 1 M aqueous HCl in THF
resulted in the formation of 1-hydroxy-3-trichloroacetic amide
derivative 4 in 65% yield with no epimization of the benzylic
alcohol. Treatment of 4 with Na2CO3 under reflux in DMF
resulted in the formation of 1,3-oxazinan-2-one 5 in 83%
yield.20 Compound cis-2a could also be converted to free 1,3-
amino alcohol 6 by hydrolysis with 1 M HCl in methanol
followed by treatment with a 1 M aqueous NaOH solution.
Scheme 2. Reaction of (Z)-1a
The enantioenriched trichloroacetimidate (S)-1a, which was
prepared in two steps from (S)-1-phenylbut-3-en-1-ol,15 was
subjected to our standard conditions and formed (4R,6S)-2a
with 8.6:1 diastereoselectivity without the loss of enantiopurity
(Scheme 3).
5,6-Dihydro-1,3-oxazines could be hydrolyzed under mild
conditions, which is typically a difficult operation for related
benzenesulfonamide analogues. Furthermore, 1,3-amino alco-
hols in different protection states could be obtained selec-
tively by controlling the reaction conditions (Scheme 4).
CONCLUSION
■
A palladium(0)-catalyzed cyclization reaction of homoallylic
trichloroacetimidates to form 5,6-dihydro-1,3-oxazines has
been reported. The stereoselectivity is sensitive to the steric
bulk adjacent to the trichloroacetimidate group, and diaste-
reoselectivites of up to >20:1 favoring the cis isomers were
obtained. The resulting products are synthetic equivalents of
variably protected 1,3-amino alcohols, which are valuable
synthons for organic synthesis.
a
Table 2. Effect of the Leaving Group
b
entry
X
t (days)
% yield (cis/trans) of 2a
1
2
3
4
5
OC(NH)CCl3 (1A)
1
52 (2.0:1)
60 (3.5:1)
75 (1.3:1)
46 (3.0:1)
trace
OAc (1B)
3
OPiv (1C)
3
Cl (1D)
1.5
3
OCO2Me (1E)
a
b
The reactions were conducted on a 0.20 mmol scale of 1. Isolated yields.
C
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a
Table 3. Substrate Scope
a
b
The reactions were conducted on a 0.17−0.24 mmol scale of 1 (see the Supporting Information for details). 7.5 mol % Pd(dba)2 was used.
Scheme 3. Synthesis of (4R,6S)-2a
an atmosphere of nitrogen. All other solvents and reagents were used as
obtained from commercial sources without further purification. Melting
EXPERIMENTAL SECTION
General Information. Reactions were performed under an inert
atmosphere of dry nitrogen in flame-dried glassware, unless stated other-
wise. Anhydrous solvents were distilled using standard techniques. THF
and Et2O were distilled over sodium under an atmosphere of nitrogen.
PhMe, DMF, DCM, and Et3N were distilled over calcium hydride under
■
points were uncorrected. NMR spectra were recorded in CDCl3 or
MeOH-d4 (1H at 400 MHz and 13C at 100 MHz) using TMS as the
internal standard. Column chromatography was performed on silica gel
(40−63 μm). Room-temperature reactions were performed at 25 1 °C.
D
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Scheme 4. Deprotection Studies
Representative Procedure for Olefin Metathesis (Typical
Procedure A).
The compound (Rf = 0.15, PE/EA 10:1) (1.25 g, 66%, E/Z ∼11:1)
was prepared following Typical Procedure A on a 6.0 mmol scale as a
1
brown oil: H NMR (400 MHz, CDCl3) δ 7.32 (d, J = 8.4 Hz, 2H),
7.27 (d, J = 8.4 Hz, 2H), 5.82−5.62 (m, 2H), 4.71 (t, J = 6.4 Hz, 1H),
4.51 (d, J = 6.4 Hz, 2H), 2.48 (t, J = 6.8 Hz, 2H), 2.25 (br s, 1H), 1.49
(s, 9H); 13C NMR (100 MHz, CDCl3) δ 153.3, 142.2, 133.2, 131.3,
128.5, 127.6, 127.1, 82.1, 72.6, 67.1, 42.1, 27.7; HRMS (Orbitrap ESI)
calcd for C16H21O4ClNa [M + Na]+ 335.1021, found 335.1022.
(E)-Methyl 4-(5-((tert-Butoxycarbonyl)oxy)-1-hydroxypent-3-en-
1-yl)benzoate (7d).
Under nitrogen, to a solution of 1-phenylbut-3-en-1-ol (2.10 g,
14.2 mmol, 1.0 equiv) and (Z)-but-2-ene-1,4-diyl di-tert-butyl dicar-
bonate (8.00 g, 27.7 mmol, 2.0 equiv) in 30 mL of anhydrous CH2Cl2
was added Grubbs second-generation catalyst (0.24 g, 0.28 mmol,
0.02 equiv), and the resulting mixture was refluxed overnight. After
removal of the solvent by evaporation, the residue was purified by flash
chromatography on silica gel (petroleum ether (PE)/ethyl acetate
(EA), 10:1−5:1) to afford (E)-7a (2.07 g, 52%) as a viscous brown oil
and (Z)-7a (0.20 g, 5.1%) as a viscous brown oil.
The compound (Rf = 0.2, PE/EA 5:1) (0.56 g, 58%) was prepared
following Typical Procedure A on a 2.8 mmol scale as a colorless oil:
1H NMR (400 MHz, CDCl3) δ 7.97 (d, J = 8.4 Hz, 2H), 7.38 (d, J =
8.4 Hz, 2H), 5.79−5.62 (m, 2H), 4.76 (dd, J = 5.6, 7.2 Hz, 1H), 4.47
(d, J = 5.6 Hz, 2H), 3.88 (s, 3H), 2.50−2.43 (m, 2H), 1.45 (s, 9H);
13C NMR (100 MHz, CDCl3) δ 166.9, 153.2, 148.9, 131.1, 129.7,
129.2, 127.7, 125.6, 82.1, 72.8, 67.0, 52,0, 42.1, 27.7; HRMS (Orbitrap
ESI) calcd for C18H24O6Na [M + Na]+ 359.1465, found 359.1468.
(E)-tert-Butyl (5-Hydroxy-5-(4-nitrophenyl)pent-2-en-1-yl) Carbon-
ate (7e).
(E)-tert-Butyl (5-Hydroxy-5-phenylpent-2-en-1-yl) Carbonate [(E)-
1
7a]. H NMR (400 MHz, CDCl3) δ 7.37−7.25 (m, 5H), 5.84−5.68
(m, 2H), 4.73 (t, J = 6.8 Hz, 1H), 4.51 (dd, J = 0.8, 6.0 Hz, 2H), 2.51
(td, J = 0.8, 6.8 Hz, 1H), 1.48 (s, 9H). The NMR data were identical
to those reported previously in the literature.15
(Z)-tert-Butyl (5-Hydroxy-5-phenylpent-2-en-1-yl) Carbonate
1
[(Z)-7a]. H NMR (400 MHz, CDCl3) δ 7.42−7.22 (m, 5H), 5.76−
5.61 (m, 2H), 4.74 (dd, J = 5.2, 7.2 Hz, 1H), 4.66−4.58 (m, 1H),
4.55−4.47 (m, 1H), 2.69−2.58 (m, 1H), 2.58−2.43 (m, 2H), 1.48
(s, 9H); 13C NMR (100 MHz, CDCl3) δ 153.5, 143.8, 130.6, 128.4,
127.5, 126.2, 125.7, 82.3, 73.4, 62.6, 37.4, 27.7; HRMS (Orbitrap ESI)
calcd for C16H22O4Na [M + Na]+ 301.1410, found 301.1409.
(E)-tert-Butyl (5-(4-tert-Butylphenyl)-5-hydroxypent-2-en-1-yl)
Carbonate (7b).
The compound (Rf = 0.2, PE/EA 5:1) (1.32 g, 68%, E/Z ∼15:1) was
prepared following Typical Procedure A on a 6.0 mmol scale as a
colorless oil: 1H NMR (400 MHz, CDCl3) δ 8.17 (d, J = 8.8 Hz, 2H),
7.50 (d, J = 8.4 Hz, 2H), 5.81−5.62 (m, 2H), 4.85 (dd, J = 4.8, 8.0 Hz,
1H), 4.49 (d, J = 6.0 Hz, 2H), 2.58−2.39 (m, 3H), 1.46 (s, 9H); 13C
NMR (100 MHz, CDCl3) δ 153.3, 151.0, 147.2, 130.3, 128.4, 126.5,
123.6, 82.3, 72.3, 66.9, 42.2, 27.7. The NMR data were identical to
those reported previously in the literature.21
(E)-tert-Butyl (5-(4-Cyanophenyl)-5-hydroxypent-2-en-1-yl) Car-
bonate (7f).
The compound (Rf = 0.15, PE/EA 10:1) (1.45 g, 72%, E/Z ∼12:1)
was prepared following Typical Procedure A on a 6.0 mmol scale as a
1
brown oil: H NMR (400 MHz, CDCl3) δ 7.29 (d, J = 8.4 Hz, 2H),
7.19 (d, J = 8.4 Hz, 2H), 5.78−5.69 (m, 1H), 5.68−5.58 (m, 1H), 4.62
(t, J = 6.4 Hz, 1H), 4.44 (dd, J = 0.8, 6.0 Hz, 2H), 2.43 (t, J = 6.8 Hz,
2H), 1.95 (br s, 1H), 1.40 (s, 9H), 1.24 (s, 9H); 13C NMR (100 MHz,
CDCl3) δ 153.3, 150.5, 140.7, 132.2, 127.0, 125.5, 125.3, 82.0, 73.2,
67.2, 42.0, 34.5, 31.3, 27.7; HRMS (Orbitrap ESI) calcd for
C20H30O4Na [M + Na]+ 357.2036, found 357.2040.
The compound (Rf = 0.2, PE/EA 4:1) (1.03 g, 63%, E/Z >20:1) was
prepared following Typical Procedure A on a 5.4 mmol scale as a pale-
yellow solid: mp 104−105 °C (PE/EA); 1H NMR (400 MHz, CDCl3)
δ 7.59 (d, J = 8.4 Hz, 2H), 7.43 (d, J = 8.4 Hz, 2H), 5.80−5.60
(m, 2H), 4.77 (dd, J = 4.8, 7.6 Hz, 1H), 4.47 (d, J = 6.0 Hz, 2H),
2.51−2.40 (m, 3H), 1.45 (s, 9H); 13C NMR (100 MHz, CDCl3) δ
153.2, 149.1, 132.1, 130.5, 128.1, 126.4, 118.7, 111.0, 82.2, 72.4, 66.9,
42.1, 27.6; HRMS (Orbitrap ESI) calcd for C17H21O4NNa [M + Na]+
326.1363, found 326.1369.
(E)-tert-Butyl (5-(4-Chlorophenyl)-5-hydroxypent-2-en-1-yl) Car-
bonate (7c).
E
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1
(E)-tert-Butyl (5-Hydroxy-5-(3-methoxyphenyl)pent-2-en-1-yl)
Carbonate (7g).
oil: H NMR (400 MHz, CDCl3) δ 7.84−7.79 (m, 4H), 7.50−7.46
(m, 3H), 5.86−5.70 (m, 2H), 4.90 (t, J = 6.4 Hz, 1H), 4.51 (d, J =
6.0 Hz, 2H), 2.60 (t, J = 6.8 Hz, 2H), 2.02 (br s, 1H), 1.48 (s, 9H).
The NMR data were identical to those reported previously in the
literature.15
(E)-tert-Butyl (5-Hydroxy-5-(naphthalen-1-yl)pent-2-en-1-yl) Car-
bonate (7l).
The compound (Rf = 0.5, PE/EA 3:1) (1.10 g, 59%, E/Z >20:1) was
prepared following Typical Procedure A on a 6.0 mmol scale as a
1
brown oil: H NMR (400 MHz, CDCl3) δ 7.23 (t, J = 8.0 Hz, 1H),
6.91−6.86 (m, 2H), 6.79 (ddd, J = 1.2, 2.8, 8.4 Hz, 1H), 5.83−5.63
(m, 2H), 4.68 (t, J = 6.4 Hz, 1H), 4.48 (dd, J = 1.2, 6.4 Hz, 2H), 3.79
(s, 3H), 2.48 (dt, J = 0.8, 6.8 Hz, 2H), 2.21 (br s, 1H), 1.47 (s, 9H);
13C NMR (100 MHz, CDCl3) δ 159.6, 153.3, 145.5, 131.9, 129.4,
The compound (Rf = 0.2, PE/EA 10:1) (0.98 g, 69%) was prepared
following Typical Procedure A on a 4.3 mmol scale as a pale-brown
oil: 1H NMR (400 MHz, CDCl3) δ 8.06 (d, J = 8.0 Hz, 1H), 7.89 (d,
J = 7.6 Hz, 1H), 7.79 (d, J = 8.0 Hz, 1H), 7.66 (d, J = 7.2 Hz, 1H),
7.56−7.45 (m, 3H), 5.98−5.90 (m, 1H), 5.82−5.72 (m, 1H), 5.54 (dd,
J = 3.6, 8.4 Hz, 1H), 4.54 (dd, J = 0.8, 6.4 Hz, 2H), 2.82−2.70 (m,
1H), 2.67−2.56 (m, 1H), 1.61 (br s, 1H), 1.49 (s, 9H); 13C NMR
(100 MHz, CDCl3) δ 153.3, 139.3, 133.8, 132.3, 130.2, 129.0, 128.1,
127.3, 126.1, 125.6, 125.4, 122.9, 122.8, 82.2, 70.2, 67.3, 41.3, 27.8;
HRMS (Orbitrap ESI) calcd for C20H24O4Na [M + Na]+ 351.1567,
found 351.1571.
127.1, 118.0, 113.0, 111.2, 82.0, 73.2, 67.2, 55.1, 42.0, 27.7; HRMS
(Orbitrap ESI) calcd for C17H24O5Na [M + Na]+ 331.1516, found
331.1517.
(E)-tert-Butyl (5-Hydroxy-5-(m-tolyl)pent-2-en-1-yl) Carbonate
(7h).
The compound (Rf = 0.2, PE/EA 10:1) (1.03 g, 58%, E/Z >20:1) was
prepared following Typical Procedure A on a 6.0 mmol scale as a
brown oil: H NMR (400 MHz, CDCl3) δ 7.23 (t, J = 7.6 Hz, 1H),
(E)-tert-Butyl (5-Hydroxy-5-(o-tolyl)pent-2-en-1-yl) Carbonate
(7m).
1
7.17−7.06 (m, 3H), 5.85−5.63 (m, 2H), 4.68 (t, J = 6.4 Hz, 1H), 4.50
(dd, J = 0.8, 6.0 Hz, 2H), 2.49 (dt, J = 0.8, 6.4 Hz, 2H), 2.35 (s, 3H),
2.09 (br s, 1H), 1.48 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 153.3,
143.7, 138.0, 132.0, 128.30, 128.29, 127.1, 126.4, 122.8, 82.0, 73.4,
67.2, 42.1, 27.7, 21.4; HRMS (Orbitrap ESI) calcd for C17H24O4Na
[M + Na]+ 315.1567, found 315.1568.
The compound (Rf = 0.4, PE/EA 10:1) (1.23 g, 70%, E/Z ∼10:1) was
prepared following Typical Procedure A on a 6.0 mmol scale as a
(E)-tert-Butyl (5-(3-Chlorophenyl)-5-hydroxypent-2-en-1-yl) Car-
bonate (7i).
1
brown oil: H NMR (400 MHz, CDCl3) δ 7.46 (d, J = 7.6 Hz, 1H),
7.25−7.09 (m, 3H), 5.89−5.81 (m, 1H), 5.79−5.66 (m, 1H), 4.96 (dd,
J = 4.8, 8.0 Hz, 1H), 4.52 (d, J = 6.4 Hz, 2H), 2.51−2.40 (m, 2H), 2.32
(s, 3H), 1.98 (br s, 1H), 1.48 (s, 9H); 13C NMR (100 MHz, CDCl3) δ
153.3, 141.8, 134.3, 132.2, 130.3, 127.3, 127.1, 126.3, 125.1, 82.1, 69.7,
67.2, 41.0, 27.7, 19.0; HRMS (Orbitrap ESI) calcd for C17H24O4Na
[M + Na]+ 315.1567, found 315.1568.
The compound (Rf = 0.2, PE/EA 10:1) (1.16 g, 62%, E/Z >20:1) was
prepared following Typical Procedure A on a 6.0 mmol scale as a
brown oil: 1H NMR (400 MHz, CDCl3) δ 7.41−7.32 (m, 1H), 7.32−
7.16 (m, 3H), 5.83−5.61 (m, 2H), 4.69 (dd, J = 5.6, 7.2 Hz, 1H), 4.50
(d, J = 6.0 Hz, 2H), 2.54−2.41 (m, 2H), 2.35 (br s, 1H), 1.48 (s, 9H);
13C NMR (100 MHz, CDCl3) δ 153.3, 145.8, 134.3, 131.2, 129.6,
(E)-tert-Butyl (5-(2,4-Dichlorophenyl)-5-hydroxypent-2-en-1-yl)
Carbonate (7n).
127.63, 127.59, 125.9, 123.9, 82.1, 72.6, 67.0, 42.1, 27.7; HRMS
(Orbitrap ESI) calcd for C16H21O4ClNa [M + Na]+ 335.1021, found
335.1027.
The compound (Rf = 0.3, PE/EA 5:1) (1.17 g, 73%) was prepared
following Typical Procedure A on a 6.0 mmol scale as a pale-yellow
oil: 1H NMR (400 MHz, CDCl3) δ 7.49 (d, J = 8.4 Hz, 1H), 7.33 (d,
J = 2.0 Hz, 1H), 7.26 (dd, J = 2.4, 8.4 Hz, 1H), 5.86−5.79 (m, 1H),
5.74−5.67 (m, 1H), 5.09 (dd, J = 4.0, 8.4 Hz, 1H), 4.51 (d, J = 6.4 Hz,
2H), 2.63−2.51 (m, 1H), 2.38−2.27 (m, 1H), 2.15 (br s, 1H), 1.47
(s, 9H); 13C NMR (100 MHz, CDCl3) δ 153.3, 139.7, 133.5, 132.1,
131.1, 129.0, 128.1, 127.9, 127.3, 82.2, 69.3, 67.1, 40.3, 27.7; HRMS
(Orbitrap ESI) calcd for C16H20O4Cl2Na [M + Na]+ 369.0631, found
369.0631.
(E)-tert-Butyl (5-Hydroxy-5-(3-nitrophenyl)pent-2-en-1-yl) Carbon-
ate (7j).
The compound (Rf = 0.2, PE/EA 5:1) (1.18 g, 60%, E/Z >20:1) was
prepared following Typical Procedure A on a 6.0 mmol scale as a
colorless oil: 1H NMR (400 MHz, CDCl3) δ 8.19 (t, J = 2.0 Hz, 1H),
8.08 (ddd, J = 1.2, 2.4, 8.4 Hz, 1H), 7.66 (d, J = 7.6 Hz, 1H), 7.49 (t,
J = 8.0 Hz, 1H), 5.81−5.63 (m, 2H), 4.83 (t, J = 6.0 Hz, 1H), 4.48 (d,
J = 6.4 Hz, 2H), 2.72 (br s, 1H), 2.56−2.41 (m, 2H), 1.44 (s, 9H); 13C
NMR (100 MHz, CDCl3) δ 153.2, 148.2, 145.9, 131.9, 130.5, 129.3,
128.2, 122.4, 120.7, 82.2, 72.1, 66.9, 42.2, 27.6; HRMS (Orbitrap ESI)
calcd for C16H21O6NNa [M + Na]+ 346.1261, found 346.1262.
(E)-tert-Butyl (5-Hydroxy-5-(naphthalen-2-yl)pent-2-en-1-yl) Car-
bonate (7k).
(E)-tert-Butyl (5-Hydroxy-7-phenylhept-2-en-1-yl) Carbonate
(7o).
The compound (Rf = 0.3, PE/EA 5:1) (1.17 g, 64%) was prepared
following Typical Procedure A on a 6.0 mmol scale as a brown oil: 1H
NMR (400 MHz, CDCl3) δ 7.35−7.18 (m, 5H), 5.88−5.77 (m, 1H),
5.75−5.66 (m, 1H), 4.54 (d, J = 6.0 Hz, 2H), 3.75−3.66 (m, 1H),
2.87−2.64 (m, 2H), 2.38−2.17 (m, 2H), 1.86 (br s, 1H), 1.84−1.75
(m, 2H), 1.51 (s, 9H). The NMR data were identical to those reported
previously in the literature.15
The compound (Rf = 0.2, PE/EA 10:1) (1.21 g, 62%) was prepared
following Typical Procedure A on a 6.0 mmol scale as a pale-brown
F
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(E)-tert-Butyl (5-Cyclohexyl-5-hydroxypent-2-en-1-yl) Carbonate
(7p).
2.91−2.80 (m, 1H), 2.78−2.67 (m, 1H), 1.48 (s, 9H); 13C NMR
(100 MHz, CDCl3) δ 161.3, 153.3, 139.2, 128.8, 128.4, 128.0, 126.6,
126.0, 91.5, 82.0, 79.7, 62.4, 34.8, 27.7; HRMS (Orbitrap ESI) calcd
for C18H22O4NCl3Na [M + Na]+ 444.0507, found 444.0500.
(E)-5-Phenylpent-2-ene-1,5-diyl Bis(2,2,2-trichloroacetimidate)
(1A).
The compound (Rf = 0.2, PE/EA 10:1) (1.21 g, 71%) was prepared
following Typical Procedure A on a 6.0 mmol scale as a colorless oil:
1H NMR (400 MHz, CDCl3) δ 5.90−5.76 (m, 1H), 5.72−5.63
(m, 1H), 4.52 (d, J = 6.4 Hz, 2H), 3.42−3.36 (m, 1H), 2.35−2.26
(m, 1H), 2.19−2.08 (m, 1H), 1.85−1.62 (m, 5H), 1.47 (s, 9H), 1.39−
0.97 (m, 6H). The NMR data were identical to those reported pre-
viously in the literature.15
(E)-tert-Butyl ((S)-5-((R)-2,2-Dimethyl-1,3-dioxolan-4-yl)-5-
hydroxypent-2-en-1-yl) Carbonate (7q).
To a solution of (E)-5-phenylpent-2-ene-1,5-diol8a (0.49 g, 2.75 mmol,
1.0 equiv) and Cl3CCN (1.1 mL, 11 mmol, 4.0 equiv) in dichloro-
methane (10 mL) was added DBU (0.1 mL, 0.67 mmol, 0.2 equiv),
and the mixture was stirred at room temperature overnight. After
removal of the solvent in vacuo, the residue was purified by flash
chromatography on silica gel (1% Et3N in PE/EA 20:1) to afford 1A
The compound (Rf = 0.15, PE/EA 5:1) (0.27 g, 63%) was prepared
following Typical Procedure A on a 1.4 mmol scale as a pale-yellow
oil: [α]2D5 = +5.4 (c 1.0, CHCl3); H NMR (400 MHz, CDCl3) δ
1
1
(1.01 g, 78%) as a white solid. Mp 65−66 °C (PE/EA); H NMR
5.88−5.78 (m, 1H), 5.76−5.67 (m, 1H), 4.53 (d, J = 6.4 Hz, 2H),
4.04−3.96 (m, 2H), 3.91 (t, J = 9.6 Hz, 1H), 3.81−3.73 (m, 1H),
2.38−2.28 (m, 1H), 2.25−2.15 (m, 1H), 1.97 (d, J = 3.2 Hz, 1H), 1.48
(s, 9H), 1.42 (s, 3H), 1.36 (s, 3H); 13C NMR (100 MHz, CHCl3) δ
153.3, 131.3, 127.4, 109.1, 82.2, 78.0, 70.5, 67.1, 65.2, 36.0, 27.8, 26.5,
25.2; HRMS (Orbitrap ESI) calcd for C15H26O6Na [M + Na]+
325.1622, found 325.1618.
(400 MHz, CDCl3) δ 8.32 (s, 1H), 8.30 (s, 1H), 7.46−7.28 (m, 5H),
5.92 (dd, J = 5.2, 8.0 Hz, 1H), 5.91−5.76 (m, 2H), 4.75 (d, J = 5.6 Hz,
2H), 2.90−2.78 (m, 1H), 2.76−2.61 (m, 1H); 13C NMR (100 MHz,
CDCl3) δ 162.4, 161.3, 139.3, 130.1, 128.4, 128.0, 126.8, 126.1, 91.5,
91.3, 79.6, 69.2, 39.5; HRMS (Orbitrap ESI) calcd for
C15H14O2N2Cl6Na [M + Na]+ 486.9079, found 486.9071.
(E)-5-Chloro-1-phenylpent-3-en-1-yl 2,2,2-Trichloroacetimidate
(1D).
Representative Procedure for the Synthesis of Trichloro-
acetimidates (Typical Procedure B).
The compound (Rf = 0.5, PE/EA 20:1) (0.36 g, 73%) was obtained
following Typical Procedure B on a 1.4 mmol scale as a pale-yellow oil:
1H NMR (400 MHz, CDCl3) δ 8.32 (s, 1H), 7.48−7.29 (m, 5H), 5.89
(dd, J = 5.2, 8.0 Hz, 1H), 5.84−5.66 (m, 2H), 4.00 (d, J = 6.0 Hz, 2H),
2.85−2.75 (m, 1H), 2.72−2.61 (m, 1H); 13C NMR (100 MHz,
CDCl3) δ 161.4, 139.3, 129.8, 129.5, 128.4, 128.1, 126.1, 91.6, 79.6,
44.8, 39.3; HRMS (Orbitrap ESI) calcd for C13H13ONCl4Na [M + Na]+
361.9644, found 361.9641.
To a solution of (E)-tert-butyl (5-hydroxy-5-phenylpent-2-en-1-yl)
carbonate [(E)-7a] (834 mg, 3.0 mmol, 1.0 equiv) and Cl3CCN
(0.6 mL, 6.0 mmol, 2.0 equiv) in dichloromethane (15 mL) was added
DBU (90 μL, 0.6 mmol, 0.02 equiv), and the mixture was stirred at
room temperature overnight. After removal of the solvent in vacuo, the
residue was purified by flash chromatography on silica gel (1% Et3N in
(E)-5-((Methoxycarbonyl)oxy)-1-phenylpent-3-en-1-yl 2,2,2-
Trichloroacetimidate (1E).
1
PE/EA 40:1) to afford (E)-1a (995 mg, 86%) as a pale-yellow oil. H
NMR (400 MHz, CDCl3) δ 8.29 (s, 1H), 7.44−7.28 (m, 5H), 5.86
(dd, J = 5.2, 8.0 Hz, 1H), 5.83−5.74 (m, 1H), 5.74−5.65 (m, 1H),
4.48 (d, J = 5.6 Hz, 2H), 2.87−2.72 (m, 1H), 2.72−2.57 (m, 1H), 1.48
(s, 9H); 13C NMR (100 MHz, CDCl3) δ 161.4, 153.3, 139.4, 130.3,
128.4, 128.1, 127.5, 126.1, 91.6, 82.0, 79.7, 67.1, 39.6, 27.7; HRMS
(Orbitrap ESI) calcd for C18H22O4NCl3Na [M + Na]+ 444.0507,
found 444.0499.
The compound (Rf = 0.5, PE/EA 20:1) (0.67 g, 58%) was obtained
following Typical Procedure B on a 3.0 mmol scale as a colorless oil:
1H NMR (400 MHz, CDCl3) δ 8.31 (s, 1H), 7.44−7.27 (m, 5H), 5.89
(dd, J = 5.2, 8.0 Hz, 1H), 5.86−5.76 (m, 1H), 5.75−5.64 (m, 1H),
4.56 (d, J = 6.4 Hz, 2H), 3.77 (s, 3H), 2.85−2.73 (m, 1H), 2.72−2.59
(m, 1H); 13C NMR (100 MHz, CDCl3) δ 161.3, 155.5, 139.3, 130.7,
128.4, 128.0, 127.1, 126.0, 91.5, 79.5, 67.9, 54.6, 39.4; HRMS
(Orbitrap ESI) calcd for C15H16O4NCl3Na [M + Na]+ 402.0037,
found 402.0031.
(Z)-5-((tert-Butoxycarbonyl)oxy)-1-phenylpent-3-en-1-yl 2,2,2-
Trichloroacetimidate [(Z)-1a].
(E)-5-Phenyl-5-(2,2,2-trichloro-1-iminoethoxy)pent-2-en-1-yl Ac-
etate (1B).
The compound (Rf = 0.5, PE/EA 20:1) (0.18 g, 79%) was obtained
following Typical Procedure B on a 0.54 mmol scale as a colorless oil:
1H NMR (400 MHz, CDCl3) δ 8.32 (s, 1H), 7.45−7.27 (m, 5H), 5.87
(dd, J = 5.6, 7.6 Hz, 1H), 5.76−5.63 (m, 2H), 4.56−4.49 (m, 2H),
G
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The compound (Rf = 0.5, PE/EA 20:1) (0.42 g, 79%) was obtained
following Typical Procedure B on a 1.4 mmol scale as a colorless oil:
1H NMR (400 MHz, CDCl3) δ 8.30 (s, 1H), 7.47−7.28 (m, 5H), 5.88
(dd, J = 5.2, 8.0 Hz, 1H), 5.83−5.72 (m, 1H), 5.72−5.63 (m, 1H),
4.49 (d, J = 6.0 Hz, 2H), 2.84−2.72 (m, 1H), 2.71−2.58 (m, 1H), 2.04
(s, 3H); 13C NMR (100 MHz, CDCl3) δ 170.6, 161.3, 139.4, 129.9,
128.4, 128.0, 127.7, 126.1, 91.5, 79.6, 64.6, 39.5, 20.9; HRMS
(Orbitrap ESI) calcd for C15H16O3NCl3Na [M + Na]+ 386.0088,
found 386.0084.
1H NMR (400 MHz, CDCl3) δ 8.31 (s, 1H), 8.03 (d, J = 8.8 Hz, 2H),
7.44 (d, J = 8.0 Hz, 2H), 5.89 (dd, J = 5.2, 8.0 Hz, 1H), 5.82−5.63 (m,
2H), 4.47 (dd, J = 0.8, 6.0 Hz, 2H), 3.90 (s, 3H), 2.82−2.71 (m, 1H),
2.70−2.60 (m, 1H), 1.47 (s, 9H); 13C NMR (100 MHz, CDCl3) δ
166.7, 161.3, 153.2, 144.4, 129.9, 129.8, 129.6, 128.0, 126.0, 91.3, 82.1,
79.1, 66.9, 52.1, 39.3, 27.7; HRMS (Orbitrap ESI) calcd for
C20H24O6NCl3Na [M + Na]+ 502.0561, found 502.0561.
(E)-5-((tert-Butoxycarbonyl)oxy)-1-(4-nitrophenyl)pent-3-en-1-yl
2,2,2-Trichloroacetimidate (1e).
(E)-5-Phenyl-5-(2,2,2-trichloro-1-iminoethoxy)pent-2-en-1-yl Piv-
alate (1C).
The compound (Rf = 0.5, PE/EA 5:1) (1.23 g, 85%) was obtained
following Typical Procedure B on a 3.0 mmol scale as a colorless oil:
1H NMR (400 MHz, CDCl3) δ 8.36 (s, 1H), 8.21 (d, J = 8.8 Hz, 2H),
7.54 (d, J = 8.8 Hz, 2H), 5.93 (dd, J = 5.6, 7.6 Hz, 1H), 5.80−5.63 (m,
2H), 4.47 (d, J = 5.6 Hz, 2H), 2.82−2.73 (m, 1H), 2.71−2.62 (m,
1H), 1.46 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 161.1, 153.2,
147.6, 146.6, 128.8, 128.5, 127.0, 123.8, 91.1, 82.1, 78.5, 66.7, 39.1,
27.7; HRMS (Orbitrap ESI) calcd for C18H21O6N2Cl3Na [M + Na]+
489.0357, found 489.0356.
The compound (Rf = 0.6, PE/EA 20:1) (0.63 g, 77%) was obtained
following Typical Procedure B on a 2.0 mmol scale as a colorless oil:
1H NMR (400 MHz, CDCl3) δ 8.30 (s, 1H), 7.45−7.27 (m, 5H), 5.88
(dd, J = 5.2, 8.0 Hz, 1H), 5.80−5.60 (m, 2H), 4.48 (d, J = 5.2 Hz, 2H),
2.84−2.73 (m, 1H), 2.70−2.59 (m, 1H), 1.19 (s, 9H); 13C NMR
(100 MHz, CDCl3) δ 178.1, 161.4, 139.4, 128.9, 128.4, 127.99, 127.96,
126.1, 91.6, 79.7, 64.4, 39.5, 38.7, 27.1; HRMS (Orbitrap ESI) calcd
for C18H22O3NCl3Na [M + Na]+ 428.0558, found 428.0557.
(E)-5-((tert-Butoxycarbonyl)oxy)-1-(4-tert-butylphenyl)pent-3-en-
1-yl 2,2,2-Trichloroacetimidate (1b).
(E)-5-((tert-Butoxycarbonyl)oxy)-1-(4-cyanophenyl)pent-3-en-1-
yl 2,2,2-Trichloroacetimidate (1f).
The compound (Rf = 0.5, PE/EA 5:1) (0.98 g, 92%) was obtained
following Typical Procedure B on a 2.3 mmol scale as a colorless oil:
1H NMR (400 MHz, CDCl3) δ 8.35 (s, 1H), 7.66 (d, J = 8.0 Hz, 2H),
7.49 (d, J = 8.0 Hz, 2H), 5.88 (dd, J = 5.2, 7.6 Hz, 1H), 5.80−5.61
(m, 2H), 4.48 (d, J = 5.6 Hz, 2H), 2.82−2.70 (m, 1H), 2.69−2.59
(m, 1H), 1.48 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 161.0, 153.1,
144.5, 132.2, 128.8, 128.3, 126.7, 118.4, 111.8, 91.0, 82.0, 78.6,
66.6, 39.0, 27.6; HRMS (Orbitrap ESI) calcd for C19H21O4N2Cl3Na
[M + Na]+ 469.0459, found 469.0455.
The compound (Rf = 0.5, PE/EA 20:1) (1.28 g, 75%) was obtained
following Typical Procedure B on a 3.5 mmol scale as a pale-yellow oil:
1H NMR (400 MHz, CDCl3) δ 8.28 (s, 1H), 7.37 (d, J = 8.4 Hz, 2H),
7.31 (d, J = 8.4 Hz, 2H), 5.87 (dd, J = 4.8, 8.0 Hz, 1H), 5.85−5.75 (m,
1H), 5.74−5.66 (m, 1H), 4.49 (d, J = 6.0 Hz, 2H), 2.82−2.72 (m, 1H),
2.68−2.59 (m, 1H), 1.48 (s, 9H), 1.32 (s, 9H); 13C NMR (100 MHz,
CDCl3) δ 161.4, 153.2, 150.8, 136.3, 130.5, 127.2, 125.7, 125.3, 91.6,
81.9, 79.6, 67.1, 39.6, 34.5, 31.3, 27.7; HRMS (Orbitrap ESI) calcd for
C22H30O4NCl3Na [M + Na]+ 500.1133, found 500.1130.
(E)-5-((tert-Butoxycarbonyl)oxy)-1-(3-methoxyphenyl)pent-3-en-
1-yl 2,2,2-Trichloroacetimidate (1g).
(E)-5-((tert-Butoxycarbonyl)oxy)-1-(4-chlorophenyl)pent-3-en-1-
yl 2,2,2-Trichloroacetimidate (1c).
The compound (Rf = 0.5, PE/EA 20:1) (1.0 g, 85%) was obtained
following Typical Procedure B on a 2.6 mmol scale as a pale-yellow oil:
1H NMR (400 MHz, CDCl3) δ 8.30 (s, 1H), 7.26 (t, J = 8.0 Hz, 1H),
6.97−6.93 (m, 2H), 6.83 (ddd, J = 0.8, 2.8, 8.4 Hz, 1H), 5.83 (dd, J =
5.2, 8.0 Hz, 1H), 5.82−5.64 (m, 2H), 4.48 (d, J = 6.4 Hz, 2H), 3.79
(s, 3H), 2.81−2.70 (m, 1H), 2.68−2.58 (m, 1H), 1.47 (s, 9H); 13C
NMR (100 MHz, CDCl3) δ 161.3, 159.6, 153.2, 141.1, 130.3, 129.5,
127.4, 118.3, 113.5, 111.4, 91.6, 82.0, 79.5, 67.0, 55.1, 39.6, 27.7;
HRMS (Orbitrap ESI) calcd for C19H24O5NCl3Na [M + Na]+
474.0612, found 474.0611.
The compound (Rf = 0.5, PE/EA 20:1) (1.23 g, 84%) was obtained
following Typical Procedure B on a 4.1 mmol scale as a pale-yellow oil:
1H NMR (400 MHz, CDCl3) δ 8.31 (s, 1H), 7.37−7.28 (m, 4H), 5.82
(dd, J = 5.6, 8.0 Hz, 1H), 5.79−5.63 (m, 2H), 4.47 (d, J = 5.6 Hz, 2H),
2.81−2.70 (m, 1H), 2.65−2.54 (m, 1H), 1.47 (s, 9H); 13C NMR
(100 MHz, CDCl3) δ 161.2, 153.2, 137.8, 133.8, 129.7, 128.6, 127.8,
127.6, 91.4, 82.0, 78.9, 66.9, 39.2, 27.7; HRMS (Orbitrap ESI) calcd
for C18H21O4NCl4Na [M + Na]+ 478.0117, found 478.0117.
(E)-Methyl 4-(5-((tert-Butoxycarbonyl)oxy)-1-(2,2,2-trichloro-1-
iminoethoxy)pent-3-en-1-yl)benzoate (1d).
(E)-5-((tert-Butoxycarbonyl)oxy)-1-(m-tolyl)pent-3-en-1-yl 2,2,2-
Trichloroacetimidate (1h).
The compound (Rf = 0.6, PE/EA 20:1) (1.36 g, 89%) was obtained
following Typical Procedure B on a 3.5 mmol scale as a pale-yellow oil:
1H NMR (400 MHz, CDCl3) δ 8.28 (s, 1H), 7.26−7.15 (m, 3H),
7.13−7.08 (m, 1H), 5.83−5.67 (m, 3H), 4.49 (dd, J = 0.8, 6.0 Hz, 2H),
The compound (Rf = 0.4, PE/EA 10:1) (0.51 g, 63%) was obtained
following Typical Procedure B on a 1.6 mmol scale as a pale-yellow oil:
H
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2.82−2.71 (m, 1H), 2.68−2.56 (m, 1H), 2.36 (s, 3H), 1.48 (s, 9H);
13C NMR (100 MHz, CDCl3) δ 161.4, 153.3, 139.4, 138.1, 130.5,
128.8, 128.3, 127.4, 126.7, 123.0, 91.6, 82.0, 79.8, 67.1, 39.7, 27.7, 21.5;
HRMS (Orbitrap ESI) calcd for C19H24O4NCl3Na [M + Na]+
458.0663, found 458.0662.
(m, 2H), 1.51 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 161.3,
153.2, 135.3, 133.7, 130.6, 130.0, 128.9, 128.5, 127.3, 126.3, 125.6,
125.2, 123.4, 122.9, 91.6, 81.9, 77.1, 67.0, 38.9, 27.7; HRMS
(Orbitrap ESI) calcd for C22H24O4NCl3Na [M + Na]+ 494.0663,
found 494.0663.
(E)-5-((tert-Butoxycarbonyl)oxy)-1-(o-tolyl)pent-3-en-1-yl 2,2,2-
Trichloroacetimidate (1m).
(E)-5-((tert-Butoxycarbonyl)oxy)-1-(3-chlorophenyl)pent-3-en-1-
yl 2,2,2-Trichloroacetimidate (1i).
The compound (Rf = 0.5, PE/EA 50:1) (1.11 g, 89%) was obtained
following Typical Procedure B on a 2.8 mmol scale as a pale-yellow oil:
1H NMR (400 MHz, CDCl3) δ 8.25 (s, 1H), 7.48−7.42 (m, 1H),
The compound (Rf = 0.5, PE/EA 20:1) (1.23 g, 84%) was obtained
following Typical Procedure B on a 3.1 mmol scale as a pale-yellow oil:
1H NMR (400 MHz, CDCl3) δ 8.34 (s, 1H), 7.43−7.37 (m, 1H),
7.25−7.11 (m, 3H), 6.03 (dd, J = 4.8, 8.8 Hz, 1H), 5.89−5.77 (m,
1H), 5.76−5.67 (m, 1H), 4.50 (dd, J = 0.8, 6.0 Hz, 2H), 2.81−2.70
(m, 1H), 2.62−2.53 (m, 1H), 2.42 (s, 3H), 1.49 (s, 9H); 13C NMR
(100 MHz, CDCl3) δ 161.2, 153.2, 137.9, 134.9, 130.5, 130.2, 127.8,
127.3, 126.2, 125.3, 91.6, 82.0, 76.7, 67.1, 38.7, 27.7, 19.1; HRMS
(Orbitrap ESI) calcd for C19H24O4NCl3Na [M + Na]+ 458.0663,
found 458.0660.
7.35−7.21 (m, 3H), 5.84 (dd, J = 5.2, 8.0 Hz, 1H), 5.82−5.66 (m,
2H), 4.50 (dd, J = 0.8, 6.0 Hz, 2H), 2.83−2.70 (m, 1H), 2.68−2.57
(m, 1H), 1.49 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 161.2, 153.2,
141.5, 134.4, 129.73, 129.66, 128.2, 127.9, 126.3, 124.3, 91.3, 82.0,
78.8, 66.9, 39.4, 27.7; HRMS (Orbitrap ESI) calcd for
C18H21O4NCl4Na [M + Na]+ 478.0117, found 478.0117.
(E)-5-((tert-Butoxycarbonyl)oxy)-1-(3-nitrophenyl)pent-3-en-1-yl
2,2,2-Trichloroacetimidate (1j).
(E)-5-((tert-Butoxycarbonyl)oxy)-1-(2,4-dichlorophenyl)pent-3-
en-1-yl 2,2,2-Trichloroacetimidate (1n).
The compound (Rf = 0.2, PE/EA 5:1) (0.84 g, 79%) was obtained
following Typical Procedure B on a 2.2 mmol scale as a pale-yellow oil:
1H NMR (400 MHz, CDCl3) δ 8.36 (s, 1H), 8.27 (dd, J = 2.0, 2.0 Hz,
1H), 8.17 (ddd, J = 0.8, 2.0, 8.0 Hz, 1H), 7.71 (dt, J = 0.8, 7.6 Hz, 1H),
7.54 (t, J = 8.0 Hz, 1H), 5.94 (dd, J = 5.2, 8.0 Hz, 1H), 5.83−5.64 (m,
2H), 4.48 (dd, J = 0.8, 6.0 Hz, 2H), 2.87−2.76 (m, 1H), 2.73−2.62
(m, 1H), 1.47 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 161.1, 153.2,
148.3, 141.6, 132.2, 129.5, 129.0, 128.5, 123.1, 121.2, 91.1, 82.1, 78.4,
66.8, 39.2, 27.7; HRMS (Orbitrap ESI) calcd for C18H21O6N2Cl3Na
[M + Na]+ 489.0357, found 489.0356.
The compound (Rf = 0.5, PE/EA 20:1) (1.39 g, 92%) was obtained
following Typical Procedure B on a 3.0 mmol scale as a pale-yellow oil:
1H NMR (400 MHz, CDCl3) δ 8.36 (s, 1H), 7.42 (d, J = 8.4 Hz, 1H),
7.38 (dd, J = 0.8, 2.0 Hz, 1H), 7.28−7.22 (m, 1H), 6.18 (dd, J = 5.2,
7.6 Hz, 1H), 5.88−5.77 (m, 1H), 5.74−5.64 (m, 1H), 4.48
(d, J = 6.0 Hz, 2H), 2.73−2.59 (m, 2H), 1.47 (s, 9H); 13C NMR
(100 MHz, CDCl3) δ 160.9, 153.2, 136.0, 134.1, 132.6, 129.4, 129.3,
128.0, 127.6, 127.5, 91.2, 82.0, 76.0, 66.9, 37.8, 27.7; HRMS
(Orbitrap ESI) calcd for C18H20O4NCl5Na [M + Na]+ 511.9727,
found 511.9729.
(E)-5-((tert-Butoxycarbonyl)oxy)-1-(naphthalen-2-yl)pent-3-en-1-
yl 2,2,2-Trichloroacetimidate (1k).
(E)-7-((tert-Butoxycarbonyl)oxy)-1-phenylhept-5-en-3-yl 2,2,2-
Trichloroacetimidate (1o).
The compound (Rf = 0.5, PE/EA 20:1) (1.15 g, 80%) was obtained
following Typical Procedure B on a 3.0 mmol scale as a pale-yellow oil:
1H NMR (400 MHz, CDCl3) δ 8.32 (s, 1H), 7.90−7.78 (m, 4H),
7.56−7.45 (m, 3H), 6.04 (dd, J = 5.2, 8.0 Hz, 1H), 5.89−5.79 (m,
1H), 5.78−5.69 (m, 1H), 4.49 (d, J = 6.0 Hz, 2H), 2.95−2.85 (m,
1H), 2.78−2.70 (m, 1H), 1.48 (s, 9H); 13C NMR (100 MHz, CDCl3)
δ 161.4, 153.2, 136.7, 133.1, 133.0, 130.3, 128.3, 128.1, 127.7, 127.6,
126.2, 126.1, 125.4, 123.9, 91.6, 82.0, 79.9, 67.0, 39.5, 27.7; HRMS
(Orbitrap ESI) calcd for C22H24O4NCl3Na [M + Na]+ 494.0663,
found 494.0662.
The compound (Rf = 0.5, PE/EA 10:1) (1.84 g, 68%) was obtained
following Typical Procedure B on a 3.2 mmol scale as a pale-yellow oil:
1H NMR (400 MHz, CDCl3) δ 8.22 (s, 1H), 7.23−7.05 (m, 5H),
5.77−5.65 (m, 1H), 5.64−5.54 (m, 1H), 5.02−4.93 (m, 1H), 4.41 (d,
J = 6.0 Hz, 2H), 2.77−2.65 (m, 1H), 2.63−2.52 (m, 1H), 2.50−2.31
(m, 2H), 2.03−1.79 (m, 2H), 1.39 (s, 9H); 13C NMR (100 MHz,
CDCl3) δ 162.0, 153.2, 141.3, 130.2, 128.4, 128.3, 127.3, 125.9, 91.8,
81.9, 77.5, 67.0, 35.9, 35.0, 31.4, 27.7; HRMS (Orbitrap ESI) calcd for
C20H26O4NCl3Na [M + Na]+ 472.0820, found 472.0819.
(E)-5-((tert-Butoxycarbonyl)oxy)-1-(naphthalen-1-yl)pent-3-en-1-
yl 2,2,2-Trichloroacetimidate (1l).
(E)-5-((tert-Butoxycarbonyl)oxy)-1-cyclohexylpent-3-en-1-yl
2,2,2-Trichloroacetimidate (1p).
The compound (Rf = 0.5, PE/EA 20:1) (1.27 g, 90%) was obtained
following Typical Procedure B on a 3.0 mmol scale as a colorless oil:
1H NMR (400 MHz, CDCl3) δ 8.35 (s, 1H), 8.14 (d, J = 8.4 Hz, 1H),
7.89 (dd, J = 1.6, 8.0 Hz, 1H), 7.82 (d, J = 8.4 Hz, 1H), 7.69 (d, J = 7.2
Hz, 1H), 7.61−7.44 (m, 3H), 6.68 (dd, J = 4.8, 8.4 Hz, 1H), 5.99−
5.86 (m, 1H), 5.82−5.71 (m, 1H), 4.52 (d, J = 6.4 Hz, 2H), 3.00−2.78
The compound (Rf = 0.5, PE/EA 20:1) (0.25 g, 15%) was obtained
following Typical Procedure B on a 3.8 mmol scale as a pale-yellow
1
oil along with recovered starting material (0.90 g, 82%). H NMR
(400 MHz, CDCl3) δ 8.20 (s, 1H), 5.88−5.75 (m, 1H), 5.71−5.61 (m,
1H), 4.89 (dd, J = 6.4, 11.2 Hz, 1H), 4.48 (dd, J = 1.2, 6.4 Hz, 2H),
I
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2.55−2.38 (m, 2H), 1.85 (d, J = 12.8 Hz, 1H), 1.78−1.60 (m, 5H),
1.47 (s, 9H), 1.30−1.00 (m, 5H); 13C NMR (100 MHz, CDCl3)
δ 162.4, 153.3, 131.0, 126.8, 92.1, 82.00, 81.98, 67.3, 40.4, 33.3,
28.8, 28.0, 27.8, 26.3, 26.0, 25.9; HRMS (Orbitrap ESI) calcd for
C18H28O4NCl3Na [M + Na]+ 450.0976, found 450.0976.
( )-(4R,6S)-6-(4-tert-Butylphenyl)-2-trichloromethyl-4-vinyl-5,6-
dihydro-4H-1,3-oxazine (cis-2b).
(S,E)-5-((tert-Butoxycarbonyl)oxy)-1-((R)-2,2-dimethyl-1,3-dioxolan-
4-yl)pent-3-en-1-yl 2,2,2-Trichloroacetimidate (1q).
The mixture of diastereomers (Rf = 0.5, PE/EA 30:1) (60.5 mg, 83%,
dr 8.4:1) was obtained following Typical Procedure C on a 0.20 mmol
1
scale as a colorless oil. Data for the major diastereomer cis-2b: H
NMR (400 MHz, CDCl3) δ 7.45 (d, J = 8.4 Hz, 2H), 7.33 (d, J =
8.4 Hz, 2H), 6.00 (ddd, J = 5.2, 10.4, 17.2 Hz, 1H), 5.41 (ddd, J = 1.2,
1.2, 16.8 Hz, 1H), 5.35 (dd, J = 2.8, 11.6 Hz, 1H), 5.21 (ddd, J = 1.2,
1.2, 10.4 Hz, 1H), 4.37−4.29 (m, 1H), 2.35 (ddd, J = 2.8, 4.8, 14.4 Hz,
1H), 1.70 (ddd, J = 11.6, 11.6, 14.0 Hz, 1H), 1.34 (s, 9H); 13C NMR
(100 MHz, CDCl3) (selected peaks) δ 153.9, 151.7, 138.1, 135.9,
125.7, 125.5, 115.4, 92.5, 79.0, 55.6, 35.7, 34.6, 31.3; HRMS (TOF EI)
calcd for C17H20ONCl3 [M]+ 359.0610, found 359.0610.
The compound (Rf = 0.3, PE/EA 10:1) (0.27 g, 73%) was obtained
following Typical Procedure B on a 0.8 mmol scale as a colorless oil
along with recovered starting material (30 mg, 12%): [α]2D5 = +16.8
1
(c 1.0, CHCl3); H NMR (400 MHz, CDCl3) δ 8.38 (s, 1H), 5.87−
5.76 (m, 1H), 5.76−5.66 (m, 1H), 5.15−5.07 (m, 1H), 4.49 (d, J =
6.0 Hz, 2H), 4.23 (dd, J = 6.0, 12.8 Hz, 1H), 4.06 (dd, J = 6.4, 8.8 Hz,
1H), 3.88 (dd, J = 5.6, 8.4 Hz, 1H), 2.71−2.60 (m, 1H), 2.56−
2.46 (m, 1H), 1.47 (s, 9H), 1.42 (s, 3H), 1.35 (s, 3H); 13C NMR
(100 MHz, CDCl3) δ 161.9, 153.3, 129.7, 127.7, 109.7, 91.4, 82.0,
77.5, 75.6, 67.1, 66.4, 33.1, 27.8, 26.6, 25.3; HRMS (Orbitrap
ESI) calcd for C17H26O6NCl3Na [M + Na]+ 468.0718, found
468.0709.
( )-(4R,6S)-6-(4-Chlorophenyl)-2-trichloromethyl-4-vinyl-5,6dihydro-
4H-1,3-oxazine (cis-2c).
Representative Procedure for Pd-Catalyzed Trichloroaceti-
midate Cyclization (Typical Procedure C).
The mixture of diastereomers (Rf = 0.4, PE/EA 20:1) (72.0 mg, 88%,
dr 7.0:1) was obtained following Typical Procedure C on a 0.24 mmol
1
scale as a pale-yellow oil. Data for the major diastereomer cis-2c: H
NMR (400 MHz, CDCl3) δ 7.39 (d, J = 8.4 Hz, 2H), 7.33 (d, J =
8.4 Hz, 2H), 5.98 (ddd, J = 5.2, 10.4, 17.2 Hz, 1H), 5.41 (ddd, J = 1.6,
1.6, 17.2 Hz, 1H), 5.34 (dd, J = 2.8, 12.0 Hz, 1H), 5.22 (ddd, J = 1.6,
1.6, 10.4 Hz, 1H), 4.37−4.27 (m, 1H), 2.34 (ddd, J = 2.8, 4.4, 14.0 Hz,
1H), 1.64 (ddd, J = 11.6, 11.6, 14.0 Hz, 1H); 13C NMR (100 MHz,
CDCl3) (selected peaks) δ 153.5, 137.8, 137.4, 134.5, 129.0, 127.0,
115.7, 92.3, 78.2, 55.4, 35.6; HRMS (TOF EI) calcd for C13H11ONCl4
[M]+ 336.9595, found 336.9590.
( )-Methyl 4-((4R,6S)-2-Trichloromethyl-4-vinyl-5,6-dihydro-4H-
1,3-oxazin-6-yl)benzoate (cis-2d).
Under nitrogen, Pd(dba)2 (5.75 mg, 0.01 mmol, 0.05 equiv) was added
to a solution of trichloroacetimidate (E)-1a (0.20 mmol, 1.0 equiv) in
anhydrous THF (2 mL), and the mixture was stirred at 20 °C for 2.5
days. The mixture was filtered through a Celite pad, and the filtrate
was concentrated. The residue was purified by flash chromatog-
raphy on a short silica gel column (1% Et3N in PE/EA 40:1) to
afford a mixture of diastereomers cis-2a and trans-2a (combined
yield 54.8 mg, 90%; dr 8.5:1) as colorless oil. This mixture of
diastereomers was separated by flash chromatography on silica gel
(1% Et3N in PE/toluene 1:2) to afford the pure diastereomers cis-2a
and trans-2a.
The mixture of diastereomers (Rf = 0.3, PE/EA 10:1) (71.7 mg, 91%,
dr 7.1:1) was obtained following Typical Procedure C on a 0.21 mmol
scale as a colorless oil. Data for the major diastereomer cis-2d: H
1
NMR (400 MHz, CDCl3) δ 8.08 (d, J = 8.4 Hz, 2H), 7.46 (d, J =
8.4 Hz, 2H), 5.97 (ddd, J = 5.2, 10.4, 16.8 Hz, 1H), 5.45−5.36 (m,
2H), 5.21 (ddd, J = 1.6, 1.6, 10.4 Hz, 1H), 4.38−4.30 (m, 1H), 3.92 (s,
3H), 2.37 (ddd, J = 2.8, 4.4, 14.0 Hz, 1H), 1.64 (ddd, J = 11.6, 11.6,
14.4 Hz, 1H); 13C NMR (100 MHz, CDCl3) (selected peaks) δ 166.5,
153.3, 143.8, 137.7, 130.3, 130.1, 125.4, 115.7, 92.2, 78.3, 55.4, 52.2,
35.5; HRMS (Orbitrap ESI) calcd for C15H15O3NCl3 [M + H]+
362.0112, found 362.0112.
( )-(4R,6S)-6-Phenyl-2-trichloromethyl-4-vinyl-5,6-dihydro-4H-
1
1,3-oxazine (cis-2a). White solid, mp 98−99 °C (PE/EA); H NMR
(400 MHz, CDCl3) δ 7.46−7.33 (m, 5H), 5.99 (ddd, J = 5.2, 10.4,
17.2 Hz, 1H), 5.45−5.34 (m, 2H), 5.21 (ddd, J = 1.6, 1.6, 10.4 Hz,
1H), 4.39−4.29 (m, 1H), 2.35 (ddd, J = 2.8, 4.8, 14.0 Hz, 1H), 1.68
(ddd, J = 11.6, 11.6, 14.0 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ
153.8, 139.0, 138.1, 128.8, 128.6, 125.6, 115.5, 92.4, 79.0, 55.6, 35.8;
HRMS (Orbitrap ESI) calcd for C13H13ONCl3 [M + H]+ 304.0057,
found 304.0059.
( )-(4R,6S)-6-(4-Nitrophenyl)-2-trichloromethyl-4-vinyl-5,6-dihy-
dro-4H-1,3-oxazine (cis-2e) and ( )-(4S,6S)-6-(4-Nitrophenyl)-2-
trichloromethyl-4-vinyl-5,6-dihydro-4H-1,3-oxazine (trans-2e).
( )-(4S,6S)-6-Phenyl-2-trichloromethyl-4-vinyl-5,6-dihydro-4H-
1,3-oxazine (trans-2a). Colorless oil; 1H NMR (400 MHz, CDCl3) δ
7.47−7.30 (m, 5H), 6.01 (ddd, J = 4.8, 10.4, 17.2 Hz, 1H), 5.34 (ddd,
J = 1.2, 1.2, 10.4 Hz, 1H), 5.30 (dd, J = 6.4, 7.2 Hz, 1H), 5.19 (ddd, J =
1.2, 2.0, 17.2 Hz, 1H), 4.45−4.32 (m, 1H), 2.10−1.96 (m, 2H); 13C
NMR (100 MHz, CDCl3) δ 154.5, 139.2, 137.7, 128.8, 128.4, 125.5,
117.2, 92.4, 75.3, 52.9, 33.2; HRMS (Orbitrap ESI) calcd for
C13H13ONCl3 [M + H]+ 304.0057, found 304.0057.
The mixture of diastereomers (Rf ≈ 0.3, PE/EA 10:1) (67.1 mg, 95%,
dr 3.6:1) was obtained following Typical Procedure C on a 0.20 mmol
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scale as a colorless oil and then separated by flash chromatography on
silica gel (1% Et3N in PE/ethyl ether 3:1) to afford the pure dia-
stereomers cis-2e and trans-2e.
1H NMR (400 MHz, CDCl3) δ 7.31 (t, J = 8.0 Hz, 1H), 7.23−7.14
(m, 3H), 5.99 (ddd, J = 5.2, 10.4, 16.8 Hz, 1H), 5.41 (ddd, J = 1.6,
2.8, 17.2 Hz, 1H), 5.33 (dd, J = 2.8, 12.0 Hz, 1H), 5.21 (dd, J = 0.8,
10.4 Hz, 1H), 4.38−4.28 (m, 1H), 2.39 (s, 3H), 2.34 (ddd, J = 2.8, 4.4,
14.0 Hz, 1H), 1.69 (ddd, J = 11.6, 11.6, 14.0 Hz, 1H); 13C NMR
(100 MHz, CDCl3) (selected peaks) δ 153.8, 138.9, 138.5, 138.1,
129.3, 128.7, 126.3, 122.7, 115.4, 92.4, 79.1, 55.6, 35.7, 21.5; HRMS
(Orbitrap ESI) calcd for C14H15ONCl3 [M + H]+ 318.0214, found
318.0214.
Data for cis-2e: 1H NMR (400 MHz, CDCl3) δ 8.29 (d, J = 8.8 Hz,
2H), 7.58 (dd, J = 0.8, 8.8 Hz, 2H), 5.98 (ddd, J = 5.2, 10.4, 17.2 Hz,
1H), 5.49 (dd, J = 2.8, 12.0 Hz, 1H), 5.42 (ddd, J = 1.2, 1.2, 17.2 Hz,
1H), 5.24 (ddd, J = 1.2, 1.2, 10.4 Hz, 1H), 4.41−4.33 (m, 1H), 2.41
(ddd, J = 3.2, 4.8, 14.0 Hz, 1H), 1.64 (ddd, J = 11.6, 11.6, 14.0 Hz,
1H); 13C NMR (100 MHz, CDCl3) δ 153.0, 148.0, 145.9, 137.4,
126.4, 124.1, 116.0, 92.1, 77.6, 55.3, 35.4; HRMS (TOF EI) calcd for
C13H11O3N2Cl3 [M]+ 347.9835, found 347.9829.
( )-(4R,6S)-6-(3-Chlorophenyl)-2-trichloromethyl-4-vinyl-5,6-di-
hydro-4H-1,3-oxazine (cis-2i).
1
Data for trans-2e: H NMR (400 MHz, CDCl3) δ 8.28 (d, J =
8.8 Hz, 2H), 7.55 (dd, J = 0.4, 8.8 Hz, 2H), 6.02 (ddd, J = 4.8, 10.4,
17.2 Hz, 1H), 5.42−5.35 (m, 2H), 5.20 (ddd, J = 1.2, 1.6, 17.2 Hz,
1H), 4.48−4.38 (m, 1H), 2.12 (ddd, J = 3.6, 3.6, 14.0 Hz, 1H), 2.03
(ddd, J = 5.2, 10.0, 14.0 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ
153.8, 147.9, 146.1, 137.1, 126.3, 124.1, 117.9, 92.1, 74.1, 52.8, 33.1;
HRMS (TOF EI) calcd for C13H11O3N2Cl3 [M]+ 347.9835, found
347.9836.
The mixture of diastereomers (Rf = 0.5, PE/EA 20:1) (60.8 mg, 87%,
dr 6.7:1) was obtained following Typical Procedure C on a 0.20 mmol
scale as a colorless oil. Data for the major diastereomer cis-2i: H
( )-4-((4R,6S)-2-Trichloromethyl-4-vinyl-5,6-dihydro-4H-1,3-oxazin-
6-yl)benzonitrile (cis-2f).
1
NMR (400 MHz, CDCl3) δ 7.40−7.31 (m, 3H), 7.30−7.26 (m, 1H),
5.98 (ddd, J = 5.2, 10.4, 17.2 Hz, 1H), 5.41 (ddd, J = 1.6, 1.6, 17.2 Hz,
1H), 5.34 (dd, J = 2.8, 11.6 Hz, 1H), 5.22 (ddd, J = 1.6, 1.6, 10.4 Hz,
1H), 4.37−4.28 (m, 1H), 2.35 (ddd, J = 2.8, 4.4, 14.0 Hz, 1H), 1.65
(ddd, J = 11.6, 11.6, 14.0 Hz, 1H); 13C NMR (100 MHz, CDCl3)
(selected peaks) δ 153.4, 140.9, 137.8, 134.7, 130.1, 128.8, 125.8,
123.7, 115.7, 92.2, 78.1, 55.4, 35.6; HRMS (Orbitrap ESI) calcd for
C13H12ONCl4 [M + H]+ 337.9668, found 337.9669.
The mixture of diastereomers (Rf = 0.5, PE/EA 10:1) (56.3 mg, 84%,
dr 4.0:1) was obtained following Typical Procedure C on a 0.20 mmol
scale as a colorless oil. Data for the major diastereomer cis-2f: H
( )-(4R,6S)-6-(3-Nitrophenyl)-2-trichloromethyl-4-vinyl-5,6-dihy-
dro-4H-1,3-oxazine (cis-2j).
1
NMR (400 MHz, CDCl3) δ 7.72 (d, J = 8.4 Hz, 2H), 7.52 (d, J =
8.4 Hz, 2H), 5.97 (ddd, J = 5.2, 10.4, 17.2 Hz, 1H), 5.43 (dd, J = 2.8,
12.0 Hz, 1H), 5.41 (ddd, J = 1.6, 1.6, 17.2 Hz, 1H), 5.23 (ddd, J = 1.6,
1.6, 10.4 Hz, 1H), 4.39−4.29 (m, 1H), 2.38 (ddd, J = 2.8, 4.4, 14.0 Hz,
1H), 1.61 (ddd, J = 11.6, 11.6, 14.0 Hz, 1H); 13C NMR (100 MHz,
CDCl3) (selected peaks) δ 153.0, 144.0, 137.5, 132.7, 126.2, 118.3,
115.9, 112.5, 92.1, 77.8, 55.3, 35.4; HRMS (TOF EI) calcd for
C14H11ON2Cl3 [M]+ 327.9937, found 327.9947.
The mixture of diastereomers (Rf = 0.4, PE/EA 5:1) (68.0 mg, 89%, dr
6.0:1) was obtained following Typical Procedure C on a 0.21 mmol
( )-(4R,6S)-6-(3-Methoxyphenyl)-2-trichloromethyl-4-vinyl-5,6-
dihydro-4H-1,3-oxazine (cis-2g).
1
scale as a colorless oil. Data for the major diastereomer cis-2j: H
NMR (400 MHz, CDCl3) δ 8.31−8.19 (m, 2H), 7.76 (d, J = 7.6 Hz,
1H), 7.62 (t, J = 8.0 Hz, 1H), 5.99 (ddd, J = 5.2, 10.4, 17.2 Hz, 1H),
5.49 (dd, J = 2.8, 11.6 Hz, 1H), 5.43 (ddd, J = 1.6, 1.6, 17.2 Hz, 1H),
5.24 (ddd, J = 1.6, 1.6, 10.4 Hz, 1H), 4.42−4.32 (m, 1H), 2.43 (ddd,
J = 2.8, 4.4, 14.0 Hz, 1H), 1.68 (ddd, J = 11.6, 11.6, 14.0 Hz, 1H); 13C
NMR (100 MHz, CDCl3) (selected peaks) δ 153.0, 148.5, 141.1,
137.4, 131.5, 130.0, 123.6, 120.8, 116.0, 92.1, 77.6, 55.3, 35.5; HRMS
(Orbitrap ESI) calcd for C13H12O3N2Cl3 [M + H]+ 348.9908, found
348.9907.
The mixture of diastereomers (Rf = 0.5, PE/EA 20:1) (60.5 mg, 87%,
dr 7.2:1) was obtained following Typical Procedure C on a 0.20 mmol
scale as a pale-yellow oil. Data for the major diastereomer cis-2g: H
1
( )-(4R,6S)-6-(Naphthalen-2-yl)-2-trichloromethyl-4-vinyl-5,6-di-
hydro-4H-1,3-oxazine (cis-2k).
NMR (400 MHz, CDCl3) δ 7.33 (t, J = 8.4 Hz, 1H), 6.99−6.86 (m,
3H), 5.99 (ddd, J = 5.2, 10.4, 17.2 Hz, 1H), 5.41 (ddd, J = 1.6, 1.6,
17.2 Hz, 1H), 5.35 (dd, J = 2.8, 11.6 Hz, 1H), 5.21 (ddd, J = 1.6, 1.6,
10.4 Hz, 1H), 4.37−4.28 (m, 1H), 3.82 (s, 3H), 2.35 (ddd, J = 2.8,
4.4, 14.0 Hz, 1H), 1.67 (ddd, J = 11.6, 11.6, 14.0 Hz, 1H); 13C NMR
(100 MHz, CDCl3) (selected peaks) δ 159.9, 153.7, 140.6, 138.0,
129.8, 117.8, 115.5, 113.9, 111.3, 92.4, 78.8, 55.5, 55.2, 35.7; HRMS
(Orbitrap ESI) calcd for C14H15O2NCl3 [M + H]+ 334.0163, found
334.0163.
The mixture of diastereomers (Rf = 0.5, PE/EA 20:1) (59.1 mg, 87%,
dr 6.7:1) was obtained following Typical Procedure C on a 0.19 mmol
( )-(4R,6S)-6-(m-Tolyl)-2-trichloromethyl-4-vinyl-5,6-dihydro-4H-
1,3-oxazine (cis-2h).
1
scale as a pale-yellow oil. Data for the major diastereomer cis-2k: H
NMR (400 MHz, CDCl3) δ 7.94−7.84 (m, 4H), 7.55−7.47 (m, 3H),
6.02 (ddd, J = 5.2, 10.4, 16.8 Hz, 1H), 5.54 (dd, J = 2.4, 11.6 Hz, 1H),
5.43 (ddd, J = 1.6, 1.6, 17.2 Hz, 1H), 5.23 (ddd, J = 1.2, 1.2, 10.4 Hz,
1H), 4.44−4.34 (m, 1H), 2.44 (ddd, J = 2.8, 4.4, 14.0 Hz, 1H), 1.79
(ddd, J = 11.6, 11.6, 14.0 Hz, 1H); 13C NMR (100 MHz, CDCl3)
(selected peaks) δ 153.8, 138.1, 136.2, 133.3, 133.1, 128.8, 128.1,
127.8, 126.53, 126.49, 125.0, 123.2, 115.6, 92.5, 79.2, 55.6, 35.6;
HRMS (Orbitrap ESI) calcd for C17H15ONCl3 [M + H]+ 354.0214,
found 354.0220.
The mixture of diastereomers (Rf = 0.5, PE/EA 20:1) (61.8 mg, 90%,
dr 7.4:1) was obtained following Typical Procedure C on a 0.21 mmol
scale as a pale-yellow oil. Data for the major diastereomer cis-2h:
K
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( )-(4R,6S)-6-(Naphthalen-1-yl)-2-trichloromethyl-4-vinyl-5,6-di-
hydro-4H-1,3-oxazine (cis-2l).
The mixture of diastereomers (Rf ≈ 0.4, PE/EA 20:1) (55.1 mg, 77%,
dr 2.3:1) was obtained following Typical Procedure C on a 0.21 mmol
scale as a colorless oil.
Data for cis-2o: 1H NMR (400 MHz, CDCl3) δ 7.35−7.27 (m, 2H),
7.25−7.18 (m, 3H), 5.94 (ddd, J = 5.6, 10.4, 17.2 Hz, 1H), 5.35 (ddd,
J = 1.6, 1.6, 17.2 Hz, 1H), 5.18 (ddd, J = 1.2, 1.2, 10.4 Hz, 1H), 4.32−
4.22 (m, 1H), 4.16−4.06 (m, 1H), 2.93−2.76 (m, 2H), 2.14−2.03 (m,
2H), 2.02−1.87 (m, 1H), 1.45 (ddd, J = 14.0, 11.6, 11.6 Hz, 1H); 13C
NMR (100 MHz, CDCl3) δ 153.8, 140.8, 138.4, 128.6, 128.5, 126.2,
115.2, 92.5, 76.3, 55.3, 36.7, 33.1, 30.6; HRMS (Orbitrap ESI) calcd
for C15H17ONCl3 [M + H]+ 332.0370, found 332.0368.
The mixture of diastereomers (Rf = 0.5, PE/EA 20:1) (57.4 mg, 86%,
dr 16.9:1) was obtained following Typical Procedure C on a 0.20
mmol scale as a pale-yellow oil. Data for the major diastereomer cis-2l:
1H NMR (400 MHz, CDCl3) δ 8.03−7.84 (m, 3H), 7.69 (dd, J = 0.8,
7.2 Hz, 1H), 7.61−7.49 (m, 3H), 6.12 (dd, J = 2.4, 11.6 Hz, 1H), 6.02
(ddd, J = 5.2, 10.4, 16.8 Hz, 1H), 5.44 (ddd, J = 1.2, 1.2, 17.2 Hz, 1H), 5.23
(ddd, J = 1.2, 1.2, 10.4 Hz, 1H), 4.54−4.42 (m, 1H), 2.59 (ddd, J = 2.8, 4.8,
14.4 Hz, 1H), 1.85 (ddd, J = 11.2, 11.2, 14.0 Hz, 1H); 13C NMR
(100 MHz, CDCl3) (selected peaks) δ 153.9, 138.0, 134.2, 133.7, 129.8,
129.2, 129.1, 126.6, 125.9, 125.5, 123.3, 122.3, 115.6, 92.5, 76.4, 55.9, 34.7;
HRMS (TOF EI) calcd for C17H14ONCl3 [M]+ 353.0141, found 353.0153.
( )-(4R,6S)-6-(o-Tolyl)-2-trichloromethyl-4-vinyl-5,6-dihydro-4H-
1,3-oxazine (cis-2m).
1
Data for trans-2o: H NMR (400 MHz, CDCl3) δ 7.33−7.27 (m,
2H), 7.25−7.16 (m, 3H), 5.89 (ddd, J = 4.8, 10.4, 17.2 Hz, 1H), 5.23
(ddd, J = 1.2, 1.2, 10.4 Hz, 1H), 5.10 (ddd, J = 1.2, 1.2, 17.2 Hz, 1H),
4.40−4.32 (m, 1H), 4.31−4.20 (m, 1H), 2.93−2.83 (m, 1H), 2.83−2.73
(m, 1H), 2.13−2.01 (m, 1H), 1.96−1.85 (m, 1H), 1.85−1.78 (m, 2H);
13C NMR (100 MHz, CDCl3) δ 154.4, 140.9, 138.0, 128.52, 128.47,
126.2, 116.7, 92.6, 73.2, 52.9, 36.4, 30.9, 30.6; HRMS (Orbitrap ESI)
calcd for C15H17ONCl3 [M + H]+ 332.0370, found 332.0374.
( )-(4R,6S)-6-Cyclohexyl-2-trichloromethyl-4-vinyl-5,6-dihydro-
4H-1,3-oxazine (cis-2p).
The mixture of diastereomers (Rf = 0.4, PE/EA 20:1) (46.1 mg, 82%, dr
10.5:1) was obtained following Typical Procedure C on a 0.18 mmol
scale as a colorless oil. Data for the major diastereomer cis-2p: 1H NMR
(400 MHz, CDCl3) δ 5.95 (ddd, J = 5.6, 10.4, 17.2 Hz, 1H), 5.36 (ddd,
J = 1.6, 1.6, 17.2 Hz, 1H), 5.17 (ddd, J = 1.6, 1.6, 10.4 Hz, 1H), 4.17−
4.05 (m, 2H), 2.07 (ddd, J = 2.8, 4.8, 13.6 Hz, 1H), 1.94 (d, J = 12.4 Hz,
1H), 1.81−1.59 (m, 5H), 1.42 (ddd, J = 11.6, 11.6, 14.0 Hz, 1H), 1.35−
1.04 (m, 5H); 13C NMR (100 MHz, CDCl3) δ 154.2, 138.7, 115.1, 92.6,
81.9, 55.5, 42.0, 30.1, 28.0, 27.8, 26.3, 25.9, 25.8; HRMS (Orbitrap ESI)
calcd for C13H19ONCl3 [M + H]+ 310.0527, found 310.0528.
(4R,6S)-6-((R)-2,2-Dimethyl-1,3-dioxolan-4-yl)-2-trichloromethyl-
4-vinyl-5,6-dihydro-4H-1,3-oxazine (cis-2q).
The mixture of diastereomers (Rf = 0.4, PE/EA 20:1) (59.4 mg, 93%,
dr >20:1) was obtained following Typical Procedure C on a 0.20
mmol scale as a colorless oil. Data for the major diastereomer cis-2m:
1H NMR (400 MHz, CDCl3) δ 7.42−7.31 (m, 1H), 7.24−7.17 (m, 2H),
7.16−7.09 (m, 1H), 5.93 (ddd, J = 5.2, 10.4, 17.2 Hz, 1H), 5.48 (dd, J =
2.4, 11.6 Hz, 1H), 5.34 (ddd, J = 1.2, 1.2, 16.8 Hz, 1H), 5.14 (ddd, J = 1.2,
1.2, 10.4 Hz, 1H), 4.33−4.22 (m, 1H), 2.32 (s, 3H), 2.25 (ddd, J = 2.8,
4.8, 14.4 Hz, 1H), 1.61 (ddd, J = 11.2, 11.2, 14.0 Hz, 1H); 13C NMR
(100 MHz, CDCl3) (selected peaks) δ 154.0, 138.1, 136.8, 134.7, 130.7,
128.5, 126.6, 125.4, 115.5, 92.4, 76.3, 55.8, 34.0, 19.0; HRMS (Orbitrap
ESI) calcd for C14H15ONCl3 [M + H]+ 318.0214, found 318.0216.
( )-(4R,6S)-6-(2,4-Dichlorophenyl)-2-trichloromethyl-4-vinyl-5,6-
dihydro-4H-1,3-oxazine (cis-2n).
The mixture of diastereomers (Rf = 0.2, PE/EA 20:1) (44.2 mg, 79%,
dr 4.0:1) was obtained following Typical Procedure C on a 0.17 mmol
scale as a colorless oil. Data for the major diastereomer cis-2q: [α]D25
=
1
The mixture of diastereomers (Rf = 0.5, PE/EA 40:1) (70.6 mg, 92%,
dr >20:1) was obtained following Typical Procedure C on a 0.20 mmol
scale as a colorless oil. Data for the major diastereomer cis-2n: 1H NMR
(400 MHz, CDCl3) δ 7.49 (d, J = 8.4 Hz, 1H), 7.42 (d, J = 2.0 Hz,
1H), 7.34 (dd, J = 2.0, 8.4 Hz, 1H), 5.98 (ddd, J = 4.8, 10.4, 16.8 Hz,
1H), 5.68 (dd, J = 2.8, 11.6 Hz, 1H), 5.42 (ddd, J = 1.6, 1.6, 17.2 Hz,
1H), 5.22 (ddd, J = 1.2, 1.2, 10.4 Hz, 1H), 4.41−4.30 (m, 1H), 2.51
(ddd, J = 2.8, 4.8, 14.0 Hz, 1H), 1.44 (ddd, J = 11.2, 11.2, 14.0 Hz,
1H); 13C NMR (100 MHz, CDCl3) δ 153.1, 137.6, 135.4, 134.8,
131.9, 129.4, 128.0, 127.7, 115.8, 92.2, 75.5, 55.3, 33.7; HRMS
(Orbitrap ESI) calcd for C13H11ONCl337Cl2 [M + H]+ 375.9219,
found 375.9215.
+13.5 (c 1.0, CHCl3); H NMR (400 MHz, CDCl3) δ 5.97 (ddd, J =
5.2, 10.4, 17.2 Hz, 1H), 5.38 (ddd, J = 1.2, 1.2, 17.2 Hz, 1H), 5.20
(ddd, J = 1.2, 1.2, 10.4 Hz, 1H), 4.30−4.22 (m, 1H), 4.21−4.01 (m,
4H), 2.35 (ddd, J = 2.8, 4.8, 14.0 Hz, 1H), 1.45 (s, 3H), 1.43−1.38 (m,
1H), 1.38 (s, 3H); 13C NMR (100 MHz, CDCl3) (selected peaks) δ
152.8, 138.1, 115.4, 110.1, 92.1, 77.4, 76.8, 66.2, 54.7, 29.9, 26.7, 25.2;
HRMS (Orbitrap ESI) calcd for C12H16O3NCl3Na [M + Na]+
350.0088, found 350.0084.
Compound 4.
( )-(4R,6R)-6-Phenethyl-2-trichloromethyl-4-vinyl-5,6-dihydro-
4H-1,3-oxazine (cis-2o) and ( )-(4S,6R)-6-Phenethyl-2-trichloro-
methyl-4-vinyl-5,6-dihydro-4H-1,3-oxazine (trans-2o).
To a solution of cis-2a (152 mg, 0.1 mmol) in THF (5 mL) was added
1 M HCl (5 mL), and the mixture was stirred at room temperature
until complete consumption of cis-2a as monitored by TLC analysis
(∼1 h). The resulting mixture was extracted with EtOAc, and the
combined organic layers were dried over Na2SO4, filtered, and con-
centrated. The residue was purified by flash chromatography on silica
L
dx.doi.org/10.1021/jo402681z | J. Org. Chem. XXXX, XXX, XXX−XXX

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gel (PE/EA 5:1) to afford 4 (103 mg, 65%) as a colorless oil. 1H NMR
(400 MHz, CDCl3) δ 7.40−7.28 (m, 5H), 7.23 (br s, 1H), 5.83 (ddd,
J = 5.6, 10.4, 17.2 Hz, 1H), 5.28 (ddd, J = 0.8, 1.2, 17.2 Hz, 1H), 5.22
(ddd, J = 1.2, 1.6, 10.4 Hz, 1H), 4.85 (dd, J = 4.4, 8.4 Hz, 1H), 4.60−
4.49 (m, 1H), 2.14 (ddd, J = 8.4, 8.4, 14.4 Hz, 1H), 2.04 (ddd, J = 4.4,
5.6, 14.4 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 161.4, 143.8, 136.2,
128.8, 128.1, 125.7, 116.3, 92.7, 72.5, 52.7, 42.8; HRMS (Orbitrap
ESI) calcd for C13H14O2NCl3Na [M + Na]+ 343.9982, found
343.9984.
Under nitrogen, Grubbs second-generation catalyst (19 mg, 0.03
mmol, 0.02 equiv) was added to a solution of (S)-1-phenylbut-3-en-1-
ol (218 mg, 1.47 mmol, 1.0 equiv) and (Z)-but-2-ene-1,4-diyl di-tert-
butyl dicarbonate (3) (850 mg, 2.95 mmol, 2.0 equiv) in 10 mL of
anhydrous CH2Cl2, and the resulting mixture was refluxed overnight.
After the mixture was cooled, the solvent was removed by evaporation,
and the residue was purified by flash chromatography on silica gel
(PE/EA 10:1−5:1) to afford (S,E)-tert-butyl (5-hydroxy-5-phenylpent-
2-en-1-yl) carbonate [(S)-7a] (225 mg, 55%) as a viscous brown oil
{[α]2D5 = −36.3 (c 1.0, CHCl3)}.
Compound 5.
To a solution of alcohol (S)-7a (250 mg, 0.90 mmol) and Cl3CCN
(0.18 mL, 1.8 mmol) in dichloromethane (5 mL) was added DBU
(27 mg, 0.18 mmol), and the mixture was stirred at room temperature
overnight. After removal of solvent in vacuo, the residue was purified
by flash chromatography on silica gel (1% Et3N in PE/EA 20:1) to
afford (S,E)-5-((tert-butoxycarbonyl)oxy)-1-phenylpent-3-en-1-yl
2,2,2-trichloroacetimidate [(S)-1a] (355 mg, 93%) as a yellow oil
{[α]2D5 = −27.2 (c 1.0, CHCl3)}.
Under nitrogen, Pd(dba)2 (23 mg, 0.04 mmol, 0.05 equiv) was
added to a solution of trichloroacetimidate (S)-1a (324 mg, 0.8 mmol)
in anhydrous THF (8 mL), and the mixture was stirred at 20 °C for
2.5 days. The mixture was filtered through Celite, and the filtrate was
concentrated. The residue was purified by flash chromatography on
a short silica gel column (1% Et3N in PE/EA 40:1) to afford a mix-
ture of diastereomers (combined yield 201 mg, 86%; dr 8.5:1) as a
colorless oil.
This mixture of diastereomers was separated by flash chromatog-
raphy on silica gel (1% Et3N in PE/toluene 1:2) to afford the pure
enantiomer (4R,6S)-6-phenyl-2-trichloromethyl-4-vinyl-5,6-dihydro-
4H-1,3-oxazine [(4R,6S)-2a, cis-2a] as a white solid with 98% ee as
determined by HPLC [Daicel Chiralcel OD-H column, i-PrOH/
hexane 1:99, flow rate 0.7 mL/min, tR = 11.9 min for the (4R,6S)
isomer (major) and 12.4 min for the (4S,6R) isomer (minor)]. Mp
74−75 °C (PE/EA); [α]2D5 = −69.2 (c 1.0, CHCl3).
A mixture of Na2CO3 (21 mg, 0.2 mmol, 2.0 equiv) and 4 (32.2 mg,
0.1 mmol) in DMF (1 mL) was heated at reflux for 3 h and then
cooled to room temperature. The mixture was diluted with ethyl
acetate (30 mL) and washed with water three times. The combined
organic layers were dried over Na2SO4, filtered, and concentrated. The
residue was purified by flash chromatography on silica gel (PE/EA
1:1) to afford 5 (16.5 mg, 83%) as a white solid. Mp 141−142 °C
1
(PE/EA); H NMR (400 MHz, CDCl3) δ 7.42−7.30 (m, 5H), 5.77
(ddd, J = 7.2, 10.0, 17.2 Hz, 1H), 5.66 (s, 1H), 5.38−5.27 (m, 2H),
5.23 (d, J = 10.4 Hz, 1H), 4.18 (ddd, J = 4.8, 7.2, 11.6 Hz, 1H), 2.29−
2.21 (m, 1H), 1.86 (ddd, J = 11.6, 11.6, 14.0 Hz, 1H); 13C NMR
(100 MHz, CDCl3) δ 154.0, 138.6, 136.9, 128.6, 128.5, 125.8, 117.7,
78.2, 54.0, 36.2; HRMS (TOF EI) calcd for C12H13NO2 [M]+
203.0946, found 203.0942.
Compound 6.
ASSOCIATED CONTENT
■
S
* Supporting Information
CIF file for cis-2a, NOESY spectra for cis- and trans-2a, and 1H
and 13C NMR spectra for all new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
To a solution of cis-2a (30.4 mg, 0.1 mmol) in methanol (1 mL) was
added 1 M HCl (1 mL), and the mixture was stirred until complete
consumption of the starting material as monitored by TLC analysis
(∼1 h). After the mixture was cooled to 0 °C using an ice bath, 1 M
NaOH (2 mL) was added, and the resulting mixture was stirred at
room temperature overnight. The mixture was extracted with DCM
three times, and the combined organic layers were dried over Na2SO4,
filtered, and concentrated. The residue was purified by flash chro-
matography on a short silica gel column (DCM/MeOH 10:1) to
afford free amino alcohol 6 (14.1 mg, 80%) as a colorless oil. 1H NMR
(400 MHz, MeOH-d4) δ 7.40−7.28 (m, 4H), 7.28−7.19 (m, 1H), 5.85
(ddd, J = 7.2, 10.4, 17.2 Hz, 1H), 5.21 (ddd, J = 1.2, 1.2, 17.2 Hz, 1H),
5.11 (ddd, J = 0.8, 1.2, 10.4 Hz, 1H), 4.73 (dd, J = 3.6, 9.6 Hz, 1H),
3.60−3.51 (m, 1H), 1.84 (ddd, J = 6.8, 9.6, 14.0 Hz, 1H), 1.72 (ddd,
J = 4.0, 6.8, 14.0 Hz, 1H); 13C NMR (100 MHz, MeOH-d4) δ 146.6,
142.6, 129.4, 128.3, 126.8, 115.3, 73.6, 53.9, 46.8; HRMS (Orbitrap
ESI) calcd for C11H16ON [M + H]+ 178.1226, found 178.1226.
Synthesis of Enantiopure (4R,6S)-2a from (S)-1-Phenylbut-3-
en-1-ol.
AUTHOR INFORMATION
Corresponding Author
*E-mail: zhgu@ustc.edu.cn.
Notes
■
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was financially supported by the NNSFC
(21272221), New Century Excellent Talents in University
(NCET-12-0511), and the Recruitment Program of Global
Experts. We thank Prof. A. Zakarian (UCSB, USA) for helpful
discussions and assistance with preparation of the manuscript.
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