Oxazolidines as Intermediates in the Asymmetric Synthesis of 3-Substituted and 1,3-Disubstituted Tetrahydroisoquinolines

Article abstract of DOI:10.1021/acs.joc.6b00525

A diastereoselective mercury(II)-promoted intramolecular cyclization of unsaturated aldehyde via an oxazolidine to prepare C-3-substituted tetrahydroisoquinoline is disclosed. The C-3 stereogenic center is subsequently exploited to create the C-1 stereocenter by coordination of the nucleophilic reagent to the oxygen atom of oxazolidine. Both cis- and trans-1,3-disubstituted tetrahydroisoquinolines can be readily prepared. In addition, when a cationic rhodium complex was used, intramolecular hydroamination was effected, thus avoiding mercury(II) salts and demercuration. The reaction is general and works well using aliphatic and aromatic aldehydes.

Full text of DOI:10.1021/acs.joc.6b00525

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Article
Oxazolidines as intermediates in the asymmetric synthesis
of 3- and 1,3-disubstituted tetrahydroisoquinolines
Sadagopan Raghavan, and Puspamitra Senapati
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b00525 • Publication Date (Web): 12 Jul 2016
Downloaded from http://pubs.acs.org on July 14, 2016
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Oxazolidines as intermediates in the asymmetric synthesis of 3-
and 1,3-disubstituted tetrahydroisoquinolines
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S. Raghavan* and Puspamitra Senapati
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Natural Product Chemistry, Indian Institute of Chemical Technology, Hyderabad 500007,
India
sraghavan@iict.res.in
Abstract: A diastereoselective mercury(II) promoted intramolecular cyclisation of
unsaturated aldehyde via an oxazolidine to prepare Cꢀ3 substituted tetrahydroisoquinoline, is
disclosed. The Cꢀ3 stereogenic center is subsequently exploited to create the Cꢀ1 stereocenter
by coordination of the nucleophilic reagent to the oxygen atom of oxazolidine. Both cisꢀ and
transꢀ1,3ꢀdisubstituted tetrahydroisoquinolines can be readily prepared. Also using cationic
rhodium complex intramolecular hydroamination was effected thus avoiding mercury(II)
salts and demercuration. The reaction is general and works well using aliphatic and aromatic
aldehydes.
Introduction
1,2,3,4ꢀTetrahydroisoquinolines (THIQs), Figure 1, constitute a large class of natural and
synthetic compounds with a wide diversity of biological properties.1 The diverse
pharmaceutical application of THIQs has stimulated the development of several
methodologies for the efficient preparation of these compounds. Much synthetic effort has
been devoted to the synthesis of 1ꢀsubstituited THIQs. The PictetꢀSpengler,2 Bischlerꢀ
Napieralski cyclisation/reduction,3 noble transition metal catalysed asymmetric
hydrogenation of isoquinoline or dihydroisoquinoline derivatives,4,5 asymmetric nucleophilic
addition to iminium ion of the cyclic precursor6 are the popular methods for the synthesis of
Cꢀ1 substituted THIQs. Few examples are known for the enantioselective synthesis of 1,3ꢀ
disubstituted THIQs. Diastereoselective alkylation of Cꢀ3 substituted THIQs afforded chiral
transꢀ1,3ꢀdisubstituted derivatives.7 The PictetꢀSpengler,8 intramolecular Heck,9 electrophile
induced cyclisation,10 nucleophilic addition to 3ꢀsubstituted isoquinolines followed by ionic
hydrogenation11 and three component reductive amination using an organocatalyst followed
by intramolecular Michael addition12 have been disclosed for the synthesis of 1,3ꢀ
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disubstituted THIQs. A key factor to be addressed in the synthesis of these molecules is the
control of relative and absolute stereochemistries at Cꢀ1 and Cꢀ3. Although some elegant
routes13 have been disclosed a generally applicable synthesis of 1,3ꢀdisubstituted THIQs is
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desirable.
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HO
OH OMe
OH
O
O
H
3
N
Me
NH
1
MeO
1
N
O
N
HO
OH
OH
3
NH
O
O
1
O
OH
N
Korupensamine B
transꢀ1,3ꢀdisubstituted THIQ
Solifenacin
Lemonomycin
cisꢀ1,3ꢀdisubstituted THIQ
Figure 1. Naturally occuring biologically active tetrahydroisoquinolines.
We report herein a diastereoselective electrophileꢀinduced intramolecular cyclisation of an
iminoalcohol/oxazolidine to prepare Cꢀ3 substituted THIQs, Schemeꢀ1. The Cꢀ3 stereogenic
center is subsequently exploited to create the Cꢀ1 stereocenter by nucleophilic addition to an
iminium ion.
H2N
1.
HgBr
R3
Ph
HO
H
N
1. nꢀBu3SnH, Et3B,
Toluene, ꢀ78 oC
R3
MgSO4, CH2Cl2, 12 h, rt
R1
R1
R2
2. Hg(OTFA)2, CH2Cl2, 0 oCꢀ
rt, 4 h, aq KBr
2. R4MgX, THF, ꢀ78 oC
Ph
R2
O
O
R3
3
N
R1
1
Ph
OH
R1, R2, R3, R4 = H, alkyl, Oꢀalkyl
R2
R4
Scheme 1. General route to THIQs using oxazolidine intermediates.
The key feature in this sequence is the use of the carbonyl group as an handle, which through
the oxazolidine nitrogen functions as a nucleophile to create the Cꢀ3 stereocenter, and
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subsequently through the iminium ion functions as an electrophile to create the Cꢀ1
stereocenter, both in an asymmetric fashion.
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Results and Discussion
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3-Mono-substituted THIQ and trans-1,3-disubstituted THIQ
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The synthetic study commenced with the known aldehyde 114 which was prepared
from 2ꢀiodobenzoic acid. Aldehyde 1 on reaction with (S)ꢀphenyl glycinol in
dichloromethane in the presence of anhydrous magnesium sulfate furnished an equilibrium
mixture of imino alcohol 2 and oxazolidine 3 which without characterization was used in the
next step. Reaction of the mixture of 2 and 3 in dichloromethane with a small excess of
mercuric trifluoroacetate furnished the oxazolidine 4 as a single isomer, the structure of
which was established by NOE, Schemeꢀ2. Characteristically a NOE was observed between
Hc and Hd, also Ha showed no NOE. The most stable ground state conformation of 3 would
have the hydrogen in the same plane as the allyl residue (A1,3 strain is avoided). Reꢀface
attack of mercuric trifluoroacetate onto the double bond followed by siꢀface attack by
oxazolidine moiety involving a half chair conformation would explain the formation of 4.
H2N
Hg(OTFA)2, CH2Cl2,
Ph
0 oC to rt, 4 h, then
aq KBr, 80%
HO
N
H
MgSO4, CH2Cl2,
12 h, rt
Ph
CHO
O
NH
HO
1
2
Ph
Stable ground state
conformation of 3
HgBr
Hf
He
N
HgOTFA
H
O
Hd
H
N
Ph
Hc
Ha
Ph
O
Hb
4
Scheme 2. Synthesis of oxazolidine 4 by Hg(II) promoted aminomercuration
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Reductive demercuration using tributyltin hydride and triethylborane15 cleanly afforded the
Cꢀ3 methyl substituted THIQ derivative 5. The next objective was the introduction of Cꢀ1
substituent by nucleophilic addition. Reaction of 5 with methylmagnesium iodide,
vinylmagnesium bromide and 1ꢀoctynylmagnesium chloride cleanly afforded transꢀ1,3ꢀ
disubstituted THIQ derivatives 6ꢀ8, Schemeꢀ3. The diastereoselective addition of
organomagnesium compounds to oxazolidines has been described before.8 Reduction of 4
with an excess of tributyltin hydride furnished the Cꢀ3 mono substituted derivative 9.
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2 eq nꢀBu3SnH, Et3B,
Toluene, ꢀ78 oC,
30 min. 80%
N
Ph
HO
CH3MgI, ꢀ78 oC,
9
1 h, 80%
N
Ph
OH
6
HgBr
Ph
1 eq nꢀBu3SnH, Et3B,
Toluene, ꢀ78 oC,
30 min. 80%
MgBr
N
THF, ꢀ78 oC,
1 h, 75%
N
N
Ph
OH
Ph
H
H
O
O
5
4
7
C6H13
MgCl
N
Ph
THF, ꢀ10 oC,
1 h, 85%
TEMPO, NaBH4,
DMF, O2, 0 oC,
10 min, 80%
OH
C6H13
8
N
O
OH
Zn, 50% CH3COOH,
100 oC, 1 h, 75%
N
NH
Ph
H
10
O
11
Scheme 3. Synthesis of transꢀ1,3ꢀdisubstituted THIQs and 3ꢀsubstituted THIQs.
Oxidative demercuration of 4 using NaBH4 and TEMPO16 cleanly furnished the oxygenated
derivative 10. Reduction of 10 using Zn/CH3COOH furnished Cꢀ3 hydroxy methyl derivative
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11. Compound 11 has been utilized in a diastereoselective alkylation to prepare transꢀ1,3ꢀ
disubstituted THIQ.17
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The structure of compound 6 was assigned by NOE studies. The presence of NOE
between Cꢀ1 H and Cꢀ3 Me and the absence of NOE between Cꢀ1 H and Cꢀ3 H confirmed
that both Me groups are anti to each other. The structures were assigned to compounds 7 and
8 based on analogy. The stereochemical outcome can be rationalized by postulating transition
state I wherein the phenyl group of amino alcohol would prevent nucleophilic attack to the siꢀ
face of the iminium ion while the oxygen atom of the amino alcohol moiety would coordinate
with the Grignard reagent and deliver it to the reꢀface, Schemeꢀ4.
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Ph
Ph
N
N
H
N
N
Ph
O
O
Ph
H
MgI
MgI
O
Me
Me
I
6
OH
5
Scheme 4. Model to rationalize stereoselective formation of transꢀ1,3ꢀTHIQs.
The generality of the reaction was further explored using aldehydes 12,18 14 and 16,19
Schemeꢀ5. The aminomercuration reaction proceeded in excellent yields with electron rich
aldehyde and also orthoꢀsubstitution relative to both carbonyl and allyl group is well
tolerated.
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H2N
OBn
HgBr
Ph
1.
OBn
MeO
HO
MeO
MgSO4, CH2Cl2. rt, 12 h
N
N
N
6
7
8
9
Ph
2. Hg(OTFA)2, CH2Cl2,
0 oCꢀrt, 4 h, aq KBr, 85%
H
CHO
CHO
O
13
12
OBn
HgBr
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OBn
Conditions same as above
70%
Ph
BnO
H
H
H
BnO
O
14
16
15
HgBr
Conditions same as above
82%
Ph
CHO
HO
O
17
HgBr
H
N
OTBS
OP
OH
Grubbs' II gen. cat
CH2Cl2, rt, 12 h,
Conditions same
as above
Ph
CHO
CHO
85%
O
1
TBSCl, imidazole,
CH2Cl2, 0 oC to rt,
1 h, 90%
18, P = H
19
20
, P = TBS
Scheme 5. Synthesis of a variety of organomercurials by Hg(II)ꢀpromoted cyclization.
The reaction works well with a transꢀdisubstituted alkene 19 obtained by cross metathesis of
aldehyde 1 and cisꢀ1,4ꢀbutanediol. The structures were assigned to 13, 15, 17 and 20 based
on analogy. These organomercurials can be transformed, as illustrated in Scheme 3 using
compound 4, into transꢀ1,3ꢀdisubstitued THIQs.
Racemic aliphatic aldehyde 2120 reacted under similar conditions to furnish a
diastereomeric equimolar mixture of oxazolidines 22 and 23, Scheme 6. Formation of only
two isomers can be explained by efficient 1,2ꢀasymmetric induction due to the phenyl group.
Either 22 or 23 can be selectively obtained from optically pure 21. Characteristic NOE were
observed between protons of Ha and Hb, Hb and Hc and Hd and He in compound 22 thus
establishing its structure. The structure of compound 23 should be as depicted. 2,4,5ꢀ
Trisubstituted pyrrolidine derivatives can be readily obtained by reaction of bicyclic
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compound 22 or 23 with Grignard reagents following the disclosed methodology. Also
starting from α–substituted and α,β–disubstituted,γ,δꢀunsaturated aliphatic aldehydes 2,3,5ꢀ
trisubstituted and 2,3,4,5ꢀ tetrasubstituted pyrrolidines can be obtained.
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H2N
HO
HgBr
N
HgBr
Hd
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Ph
1.
Ph
Ph
He
Hc
Ph
MgSO4, CH2Cl2. rt, 12 h
N
+
Ph
Ph
O
2. Hg(OTFA)2, CH2Cl2,
0 oCꢀrt, 4 h, aq KBr, 85%
O
O
Hb
H
Ha
23
22
21
Scheme 6. Preparation of pyrrolidine derivative from an acyclic aliphatic aldehyde.
Cis-1,3-disubstituted THIQs
Since cisꢀ1,3ꢀdisubstituted THIQs are more common in natural and synthetic
compounds we explored the stereoselective reduction of a THIQ tetrasubstituted at Cꢀ1 as a
route to cisꢀ1,3ꢀdisubstituted THIQs. Treatment of 2421 with (S)ꢀphenyl glycinol in the
presence of titanium tetraethoxide furnished presumably an imine in equillibrium with the
oxazolidine derivative, which without characterisation was subsequently reacted with
mercuric trifluoroacetate to yield oxazolidine 25 after treatment with aq potassium bromide,
Schemeꢀ7. Since compound 25 was not stable to column chromatography the crude
compound was taken ahead to demercuration. Demercuration using tributyltin hydride
furnished compound 26 cleanly. Disappointingly, reduction of oxazolidine 26 with sodium
borohydride in the presence of trifluoroacetic acid furnished the product 6. Hydride transfer
to the siꢀface of the iminium ion would account for the formation of 6. However, reduction
with alane22 furnished the cisꢀ1,3ꢀdisubstituted THIQ 27. Probably using alane the hydride
delivery takes place by coodination to the oxazolidine oxygen. The structure assigned to 27
was confirmed by the NOE studies that revealed NOE between Cꢀ1 H and Cꢀ3 H. In a similar
fashion, ketone 2823 was converted to mercuric compound 29, demercuration furnished
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oxazolidine 30, which on reduction using alane afforded the cisꢀTHIQ 31. Thus we have
developed a route to selectively prepare cisꢀ and transꢀ1,3ꢀdisubstituted THIQs.
H2N
HgBr
Ph
7
8
9
HO
Br
See ref. 14
1. Ti(OEt)4, rt, 16 h
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N
2. Hg(OTFA)2, CH2Cl2,
0 oCꢀrt, 4 h, aq KBr, 75%
Ph
O
O
O
24
25
Me
NaBH4, TFA, THF,
0 oC, 30 min, 60%
N
Ph
OH
H
nꢀBu3SnH, Et3B,
Toluene, ꢀ78 oC,
30 min. 80%
6
N
Ph
O
26
AlH3, THF, ꢀ10 oC,
30 min, 75%
H
N
Ph
H
27
OH
H2N
OBn
HgBr
Ph
OBn
Ph
OBn
nꢀBu3SnH, Et3B,
Toluene, ꢀ78 oC,
30 min. 90%
HO
1. Ti(OEt)4, rt, 16 h
MeO
MeO
MeO
N
N
2. Hg(OTFA)2, CH2Cl2,
0 oCꢀrt, 4 h, aq KBr, 80%
Ph
O
O
O
28
29
30
OBn
AlH3, THF, ꢀ10 oC,
30 min, 80%
MeO
H
N
Ph
H
31
OH
Scheme 7. Synthesis of cisꢀ1,3ꢀdisubstituted THIQs.
Catalytic hydroamination
A drawback of the methodology was the use of stoichiometric amounts of mercuric
salt for aminomercuration and tributyltin hydride for demercuration. At this point in the
research, the catalytic hydroamination reaction was envisaged as an alternate approach to
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prepare substituted THIQs. Catalytic hydroamination if successful, would circumvent the use
of both of these toxic reagents. Interestingly, the oxazolidine 32 could be obtained by
subjecting the mixture of iminoalcohol and oxazolidine, obtained from aldehyde 16 and (S)ꢀ
phenyl glycinol, to intramolecular hydroamination in the presence of Rh(COD)BF4 and
DPEphos in 1,4 dioxane,24 Scheme 8. Compound 32 was identical to the product obtained by
tributyltin hydride mediated demercuration of 17. Aldehyde 12 likewise furnished
oxazolidine 33. Thus catalytic hydroamination would be a valuable alternate route to Cꢀ3
substituted and transꢀ1,3ꢀdisubstituted THIQs avoiding stoichiometric mercuric salts and
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tributyltin hydride.
HgBr
1 eq nꢀBu3SnH, Et3B,
H2N
Toluene, ꢀ78 oC,
Ph
HO
30 min. 80%
N
N
Rh(COD)2BF4 (2.5 mol%),
DPEPhos (3 mol%),
1,4ꢀDioxane, 110oC,
12 h, 70%
Ph
Ph
CHO
H
H
O
O
32
16
17
OBn
OBn
H2N
MeO
MeO
Ph
HO
N
Rh(COD)2BF4 (2.5 mol%),
DPEPhos (3 mol%),
1,4ꢀDioxane, 110oC,
12 h, 70%
Ph
CHO
H
O
33
12
Scheme 8. Preparation of THIQ derivative by Rh(I)ꢀcatalyzed hydroamination.
Conclusion
Mercuric trifluoroacetate promoted diastereoselective preparation of 3ꢀsubstituted
THIQ from an oꢀallyl aldehyde is disclosed. The Cꢀ3 substituent serves to introduce the Cꢀ1
stereogenic center to access either 1,3ꢀtrans or 1,3ꢀcis THIQs. The oxazolidine moiety
functions both as a nucleophile and an electrophile in the creation of Cꢀ3 and Cꢀ1
stereocenters respectively. The reaction can be conducted by using catalytic amount of Rh(I)
catalyst via hydroamination reaction. Both cis and transꢀisomers of chiral 1,3ꢀdisubstituted
1,2,3,4ꢀTHIQs are found in biologically active alkaloids. The present work proposes a simple
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route to both the substitution patterns and compares favourably in terms of efficacy and scope
to previous approaches. Substituted pyrrolidine and piperidine derivatives can be likewise be
readily obtained. A simple readily available unsaturated aldehyde is converted to a complex
target structure.
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Experimental Section
Dry reactions were performed under an inert atmosphere using argon or nitrogen. All
glassware apparatus used for reactions are perfectly oven dried. Anhydrous solvents were
distilled prior to use; THF from Na and benzophenone; CH2Cl2, toluene from CaH2; MeOH
from Mg cake; CHCl3 from P2O5, acetone from KMnO4 and K2CO3. Commercial reagents
were used without purification. Column chromatography was carried out by using silica gel
(100−200 mesh). Analytical thinꢀlayer chromatography (TLC) was run on silica gel 60 F254
precoated plates (250 ꢁm thickness). Optical rotations [α]D were measured on a polarimeter
and given in 10−1 deg cm2 g−1. Infrared spectra were recorded in neat/KBr (as mentioned)
and reported in wavenumber (cm−1). Mass spectral data were obtained using MS (EI) ESI,
HRMS mass spectrometers. Highꢀresolution mass spectra (HRMS) [ESI+] were obtained
using either a TOF or a double focusing spectrometer. 1H NMR spectra were recorded at 300
or 400 or 500 MHz and 13C NMR spectra at 75 or 100 or 125 MHz in CDCl3 with the
residual solvent signal as internal standard unless otherwise mentioned, chemical shifts are in
ppm downfield from tetramethylsilane, and coupling constants (J) are reported in hertz (Hz).
The following abbreviations are used to designate signal multiplicity: s = singlet, d = doublet,
t = triplet, q = quartet, m = multiplet, br = broad.
General procedure for the preparation of organomercurials:
To a stirred solution of the aldehyde (1 eq) in anhydrous dichloromethane (1 M) was added
(S)ꢀphenyl glycinol (1.1 eq) followed by anhydrous MgSO4 (1 eq). The reaction mixture was
stirred at rt for 12 h. The reaction mixture was diluted with anhydrous dichloromethane (0.25
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M), cooled to 0 °C, mercuric trifluoroacetate (1.2 eq) was added. The reaction mixture was
gradually allowed to warm to rt, stirred further for a period of 4 h. The reaction mixture was
cooled to 0 °C, quenched by adding saturated aq KBr solution and stirred at rt for another 30
min. The resulting suspension was filtered through a pad of Celite and the Celite pad was
washed with dichloromethane (2x5 mL). The aq and organic layers were separated and the aq
layer extracted with dichloromethane (2x5 mL). The combined organic layers were washed
with saturated brine, dried and evaporated to furnish the crude compound which was purified
by column chromatography using EtOAc/hexane (v/v) as the eluent to afford pure
organomercurials.
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(((3S,5S,10bR)-3-phenyl-3,5,6,10b-tetrahydro-2H-oxazolo[2,3-a]isoquinolin-5-
yl)methyl)mercury(II) bromide (4). Following the general procedure, the imine prepared
from 2ꢀallyl benzaldehyde 1 (146 mg, 1 mmol) and (S)ꢀphenyl glycinol (151 mg, 1.1 mmol)
in the presence of anhydrous MgSO4 was reacted with mercuric trifluoroacetate (479 mg, 1.1
mmol) to afford pure 4 (436 mg, 0.8 mmol) after aq KBr treatment as a pale white solid in
80% yield after column chromatography using 10% EtOAc/hexane (v/v) as the eluent. MP:
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79ꢀ81 °C. Rf: 0.2 (10% EtOAc/hexane, v/v). [α]D = +1.9 (c 1, CH2Cl2). IR (neat): 2924,
2855, 1639, 1385, 1028, 755 cmꢀ1. 1H NMR (300 MHz, CDCl3): δ 7.43ꢀ7.01 (m, 9H), 5.53 (s,
1H), 4.38 (t, J = 8.1 Hz, 1H), 4.14 (dd, J = 8.3, 7.7 Hz, 1H), 3.63ꢀ3.53 (m, 2H), 2.80 (dd, J
=15.4, 2.8 Hz, 1H), 2.64 (dd, J = 15.4, 10.1 Hz, 1H), 2.2 (dd, J = 12.2, 4.3 Hz, 1H), 2.00 (dd,
J = 12.2, 1.5 Hz, 1H). 13C NMR (75 MHz, CDCl3): δ 142.8, 133.6, 132.3, 129.6, 128.3,
128.0, 127.6, 127.3, 126.9, 126.8, 90.8, 73.5, 68.2, 56.3, 44.1, 40.0. MS (ESI): 545 [M]+.
HRMS (ESI): m/z [M]+ calcd for C18H18NOBrHg 545.0278, found 545.0269.
(((3S,5S,10bR)-7-(benzyloxy)-8-methoxy-3-phenyl-3,5,6,10b-tetrahydro-2H-oxazolo[2,3-
a]isoquinolin-5-yl)methyl)mercury(II) bromide (13). Organomercurial 13 (578 mg, 0.85
mmol) was obtained, following the general procedure, from aldehyde 12 (282 mg, 1 mmol)
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as a white solid in 85% yield after column chromatography using 15% EtOAc/hexane (v/v) as
the eluent. MP: 143ꢀ145 °C. Rf: 0.2 (15% EtOAc/hexane, v/v). [α]D25 = +69.2 (c 1, CH2Cl2).
IR (neat): 2924, 2854, 1717, 1595, 1457, 1277, 1022, 751 cmꢀ1. 1H NMR (300 MHz, CDCl3):
δ 7.5ꢀ7.3 (m, 10H), 7.2 (d, J = 8.3 Hz, 1H), 6.94 (d, J = 8.3 Hz, 1H), 5.54 (s, 1H), 5.01 (s,
2H), 4.43 (t, J = 8.3 Hz, 1H), 4.18 (dd, J = 8.3, 7.5 Hz , 1H), 3.92 (s, 3H), 3.63 (dd, J = 9.0,
8.3 Hz, 1H), 3.47ꢀ3.39 (m, 1H), 3.0 (dd, J = 15.8, 3.0 Hz, 1H), 2.2 (dd, J = 12.0, 4.5 Hz, 1H),
2.11 (dd, J = 15.8, 9.8 Hz, 1H), 1.94 (dd, J = 12.0, 1.5 Hz, 1H). 13C NMR (75 MHz, CDCl3):
δ 152.3, 143.6, 142.7, 137.4, 129.6, 128.7, 128.4, 128.3, 127.9, 126.9, 125.4, 123.7, 111.1,
90.6, 74.7, 73.2, 68.0, 55.9, 55.8, 44.1, 33.7. MS (ESI): 682 [M+H]+. HRMS (ESI): m/z [M]+
calcd for C26H26NO3BrHg 681.0802, found 681.0792.
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The aldehyde 14 was prepared from the known methyl 3ꢀ(benzyloxy)ꢀ5ꢀ
hydroxybenzoate employing a straightforward sequence of reactions.
Methyl 3-(allyloxy)-5-(benzyloxy)benzoate (I). To a solution of methyl 3ꢀ(benzyloxy)ꢀ5ꢀ
hydroxybenzoate (2 g, 8 mmol) in anhydrous acetone (16 mL), allyl bromide (0.8 mL, 9.6
mmol) and K2CO3 (1.1 g, 8 mmol) were added. The mixture was refluxed for 3 h, inorganic
salts were removed by filtration and the solvent was evaporated to afford compound I (2 g, 7
mmol) as a red viscous liquid in 87% yield. Rf: 0.2 (10% EtOAc/hexane, v/v). IR (neat):
2948, 1722, 1597, 1442, 1237, 1162, 1050, 766 cmꢀ1. 1H NMR (300 MHz, CDCl3): δ 7.44ꢀ7.3
(m, 5H), 7.24 (s, 1H), 7.16 (s, 1H), 6.68 (s, 1H), 6.19ꢀ5.94 (m, 1H), 5.43ꢀ5.24 (m, 2H), 5.09
(s, 2H), 4.53 (d, J = 4.5 Hz, 2H), 3.8 (s, 3H). 13C NMR (75 MHz, CDCl3): δ 166.3, 159.2,
159.1, 136.0, 132.3, 131.5, 128.1, 127.6, 127.0, 117.4, 107.79, 107.74, 106.7, 69.7, 68.5,
51.7. MS (ESI): 299 [M+H]+. HRMS (ESI): m/z [M+H]+ calcd for C18H19O4 299.1277, found
299.1274.
Methyl 2-allyl-5-(benzyloxy)-3-hydroxybenzoate (II). A solution of methyl benzoate I (2 g,
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7 mmol) in dimethylacetamide (4 mL) was stirred at 180 C for 10 h. The cold solution was
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washed with aq 2 N NaOH solution (2x10 mL). The aq layer was washed with Et2O (10 mL),
acidified with 2 N conc. HCl and was extracted with ethyl acetate (2x20 mL). The combined
organic layers were washed with brine, dried and evaporated to afford compound II (1.4 g,
4.9 mmol) as a viscous liquid in 70% yield. Rf: 0.2 (10% EtOAc/hexane, v/v). IR (neat):
2949, 1705, 1608, 1340, 1202, 1033, 739 cmꢀ1. 1H NMR (300 MHz, CDCl3): δ 7.32ꢀ7.14 (m,
5H), 6.94 (d, J = 3 Hz, 1H), 6.49 (d, J = 3 Hz, 1H), 5.97ꢀ5.68 (m, 1H), 5.02ꢀ4.84 (m, 4H),
3.77 (s, 3H), 3.58 (d, J = 6.0 Hz, 2H). 13C NMR (75 MHz, CDCl3): δ 168.2, 157.5, 155.8,
136.6, 136.4, 131.9, 128.4, 128.1, 127.9, 127.3, 115.2, 108.7, 106.6, 70.0, 52.0, 30.4. MS
(ESI): 299 [M+H]+. HRMS (ESI): m/z [M+H]+ calcd for C18H19O4 299.1277, found
299.1275.
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Methyl 2-allyl-3,5-bis(benzyloxy)benzoate (III). To a suspension of sodium hydride (60%
in Nujol, 240 mg, 6 mmol) in anhydrous THF (10 mL) cooled at 0 °C was added nꢀ
tetrabutylammonium iodide (185 mg, 0.5 mmol) followed by the dropwise addition of a
solution of the phenol II (1.4 g, 4.9 mmol) in anhydrous THF (10 mL). The reaction mixture
was stirred allowing it to attain rt gradually over a period of 30 min. The reaction mixture
was recooled to 0 °C and neat benzyl bromide (0.7 mL, 6 mmol) was added dropwise. The
reaction mixture was stirred at rt for 6 h under an atmosphere of nitrogen and then quenched
with saturated aq NH4Cl solution (10 mL). The two layers were separated and the aqueous
layer was extracted with ethyl acetate (2x10 mL). The combined organic layers were washed
successively with water, brine and dried over Na2SO4. The solvent was evaporated under
reduced pressure and the crude product was purified by column chromatography using 5%
EtOAc/hexane (v/v) as the eluent to afford pure benzyl ether III (1.5 g, 3.9 mmol) in 80%
yield as a viscous oil. Rf: 0.2 (5% EtOAc/hexane, v/v). IR (neat): 2927, 1719, 1600, 1454,
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1234, 1054, 735 cmꢀ1. H NMR (300 MHz, CDCl3): δ 7.5ꢀ7.2 (m, 10H), 7.0 (d, J = 2.2 Hz,
1H), 6.7 (d, J = 2.2 Hz, 1H), 6.01ꢀ5.83 (m, 1H), 5.1ꢀ4.84 (m, 6H), 3.9 (s, 3H), 3.7 (d, J = 6.0
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Hz, 2H). 13C NMR (75 MHz, CDCl3): δ 168.0, 157.7, 157.4, 137.1, 136.5, 136.4, 131.8,
128.4, 128.2, 127.9, 127.7, 127.5, 127.0, 122.9, 114.4, 106.6, 104.0, 70.2, 70.1, 51.9, 30.6.
MS (ESI): 389 [M+H]+. HRMS (ESI): m/z [M+H]+ calcd for C25H25O4 389.1748, found
389.1747.
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(2-Allyl-3,5-bis(benzyloxy)phenyl)methanol (IV). To a stirred suspension of lithium
aluminium hydride (174 mg, 4.6 mmol) in anhydrous THF (20 mL) cooled at 0 °C was added
a solution of compound III (1.5 g, 3.9 mmol) in anhydrous THF (10 mL) dropwise under N2
atmosphere and allowed to warm to rt over a period of 1 h. The reaction mixture was
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recooled to 0 C and quenched by adding small ice pieces. The precipitated solids were
filtered through Celite and the solids were washed with hot EtOAc (2x10 mL). The combined
filtrates were evaporated under reduced pressure and the residue was purified by column
chromatography using 10% EtOAc/hexane (v/v) as the eluent to afford the compound IV (1.1
g, 3.3 mmol) as a yellow liquid in 85% yield. Rf: 0.2 (10% EtOAc/hexane, v/v). IR (neat):
3302, 2924, 1600, 1433, 1151, 1041, 738 cmꢀ1. 1H NMR (300 MHz, CDCl3): δ 7.41ꢀ7.13 (m,
10H), 6.57 (d, J = 2.3 Hz, 1H), 6.43 (d, J = 2.3 Hz, 1H), 5.98ꢀ5.75 (m, 1H), 4.98ꢀ4.75 (m,
6H), 4.53 (s, 2H), 3.36 (d, J = 5.4 Hz, 2H). 13C NMR (75 MHz, CDCl3): δ 158.2, 157.4,
140.9, 137.5, 137.0, 136.9, 128.53, 128.5, 127.9, 127.7, 127.5, 127.0, 118.6, 114.4, 105.5,
99.9, 70.1, 70.0, 63.1, 29.3. MS (ESI): 361 [M+H]+. HRMS (ESI): m/z [M+H]+ calcd for
C24H25O3 361.1807, found 361.1803.
2-Allyl-3,5-bis(benzyloxy)benzaldehyde (14). To a solution of oxalyl chloride (0.4 mL, 4.9
mmol) in anhydrous dichloromethane (20 mL) cooled at ꢀ78 °C was added dropwise a
solution of DMSO (0.5 mL, 6.6 mmol) in anhydrous dichloromethane (5 mL) and stirred at
the same temperature for 15 min. A solution of compound IV (1.1 g, 3.3 mmol)) in
anhydrous dichloromethane (5 mL) was added dropwise to the above mixture and stirring
continued at the same temperature for 45 min. Et3N (2.3 mL, 17 mmol) was added and the
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reaction mixture allowed to warm to ꢀ10 °C. Water (5 mL) was added, the two layers were
separated and the aqueous layer was extracted with dichloromethane (2x5 mL). The
combined organic layers were washed with water, brine and dried over Na2SO4. The solvent
was evaporated under reduced pressure and the crude product was purified by column
chromatography using 5% EtOAc/hexane (v/v) as the eluent to afford pure compound 18 (1
g, 2.9 mmol) as a red color liquid in 88% yield. Rf: 0.2 (5% EtOAc/hexane, v/v). IR (neat):
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2928, 1686, 1599, 1285, 1152, 1032, 739 cmꢀ1. H NMR (300 MHz, CDCl3): δ 10.2 (s, 1H),
7.47ꢀ7.25 (m, 10H), 7.03 (d, J = 2.2 Hz, 1H), 6.77 (d, J = 2.2 Hz, 1H), 6.08ꢀ5.9 (m, 1H),
5.16ꢀ4.82 (m, 4H), 3.8 (d, J = 5.2 Hz, 2H). 13C NMR (75 MHz, CDCl3): δ 191.4, 158.1,
157.8, 137.0, 136,4, 136.3, 135.2, 128.5, 128.0, 127.9, 127.5, 127.0, 124.9, 115.2, 106.5,
104.6, 70.5, 70.2, 27.6. MS (ESI): 359 [M+H]+. HRMS (ESI): m/z [M+H]+ calcd for
C24H23O3 359.1658, found 359.1647.
(((3S,5S,10bR)-7,9-bis(benzyloxy)-3-phenyl-3,5,6,10b-tetrahydro-2H-oxazolo[2,3-
a]isoquinolin-5-yl)methyl)mercury(II) bromide (15). Organomercurial 15 (530 mg, 0.7
mmol) was obtained from aldehyde 14 (358 mg, 1 mmol) as a white solid in 70% yield after
column chromatography using 15% EtOAc/hexane (v/v) as the eluent. MP: 69ꢀ71 °C. Rf: 0.2
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(10% EtOAc/hexane, v/v). [α]D = +21.8 (c 1, CH2Cl2). IR (neat): 2924, 1718, 1600, 1453,
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1262, 1028, 697 cmꢀ1. H NMR (300 MHz, CDCl3): δ 7.48ꢀ7.32 (m, 15H), 6.71 (d, J = 2.1
Hz, 1H), 6.58 (d, J = 2.1 Hz, 1H), 5.56 (s, 1H), 5.09ꢀ5.0 (m, 4H), 4.48 (dd, J = 8.2, 7.9 Hz,
1H), 4.24 (t, J = 8.0 Hz, 1H), 3.67 (t, J = 8.5 Hz, 1H), 3.62ꢀ3.57 (m, 1H), 3.14 (dd, J = 16.3,
3.2 Hz, 1H), 2.36 (dd, J = 16.3, 10.3 Hz, 1H), 2.3 (dd, J = 12.2, 4.4 Hz, 1H), 2.14 (dd, J =
12.2, 1.9 Hz, 1H). 13C NMR (75 MHz, CDCl3): δ 158.3, 155.8, 142.6, 136.7, 136.5, 135.7,
129.5, 128.4, 127.9, 127.5, 127.3, 127.2, 127.1, 126.8, 115.8, 103.5, 100.5, 90.7, 73.2, 70.1,
70.0, 67.9, 56.0, 32.9, 29.5. MS (ESI): 758 [M+H]+. HRMS (ESI): m/z [M+H]+ calcd for
C32H31NO3BrHg 758.1188, found 758.1162.
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The aldehyde 16 was prepared from methyl 2ꢀiodoꢀ6ꢀmethylbenzoate V in a three step
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Methyl 2-allyl-6-methylbenzoate (VI). To a solution of iꢀPrMgCl.LiCl (8.9 mL, 8.9 mmol,
1 M/THF) in anhydrous THF (9 mL) cooled at ꢀ10 °C was added the solution of compound V
(2.1 g, 8.1 mmol) in THF (3 mL) and stirred allowing the temperature to rise to 0 °C over a
period of 30 min. The reaction mixture was recooled to ꢀ10 °C and CuCN.2LiCl (0.1 mL, 1
M/THF) was added. After 5 min, allyl bromide (0.5 mL, 9.7 mmol) was added to it and
stirred at 0 °C for 1 h. The reaction was quenched by adding saturated aq NH4Cl (10 mL) and
the mixture was stirred at rt for another 30 min. The reaction mixture was extracted with
ethyl acetate (2x25 mL). The combined organic layers were washed with water, brine, dried
over Na2SO4 and evaporated to furnish the crude compound which was purified by column
chromatography using 5% EtOAc/hexane (v/v) as the eluent to afford pure compound VI (1.1
g, 6 mmol) as a colorless liquid in 75% yield. Rf: 0.5 (10% EtOAc/hexane, v/v). IR (neat):
2952, 1729, 1437, 1271, 1115, 1071, 757 cmꢀ1. 1H NMR (300 MHz, CDCl3): δ 7.27ꢀ6.98 (m,
3H), 5.94ꢀ5.8 (m, 1H), 5.08ꢀ4.96 (m, 2H), 3.86 (s, 3H), 3.35 (d, J = 6.7 Hz, 2H), 2.3 (s, 3H).
13C NMR (75 MHz, CDCl3): δ 170.1, 137.0, 136.6, 135.1, 133.5, 129.4, 128.0, 126.9, 115.9,
51.6, 38.0, 19.6. MS (ESI): 191 [M+H]+. HRMS (ESI): m/z [M+H]+ calcd for C12H15O2
191.1065, found 191.1068.
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(2-Allyl-6-methylphenyl)methanol (VII). Following the procedure detailed for the
preparation of IV, compound VII (777 mg, 4.8 mmol) was obtained from compound VI (1.1
g, 6 mmol) as a viscous liquid in 80% yield after column chromatography using 10%
EtOAc/hexane (v/v) as the eluent. Rf: 0.2 (10% EtOAc/hexane, v/v). IR (neat): 3448, 2922,
1637, 1467, 1261, 914, 770, 665 cmꢀ1. 1H NMR (300 MHz, CDCl3): δ 7.1ꢀ6.88 (m, 3H), 6.07ꢀ
5.88 (m, 1H), 5.02ꢀ4.82 (m, 2H), 4.57 (s, 2H), 3.42 (d, J = 6.0 Hz, 2H), 2.33 (s, 3H). 13C
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NMR (75 MHz, CDCl3): δ 138.6, 137.9, 136.6, 129.0, 128.1, 128.0, 115.6, 58.8, 37.5, 19.4.
MS (ESI): 163 [M+H]+.
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2-Allyl-6-methylbenzaldehyde (16). Following the procedure detailed for the preparation of
14, compound 16 (640 mg, 4 mmol) was prepared from compound VII (777 mg, 4.8 mmol)
as a colorless liquid in 85% yield after column chromatography using 10% EtOAc/hexane
(v/v) as the eluent. Rf: 0.3 (10% EtOAc/hexane, v/v). IR (neat): 2926, 1692, 1592, 1467,
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1189, 915, 734 cmꢀ1. H NMR (300 MHz, CDCl3): δ 10.43 (s, 1H), 7.23 (t, J = 7.7 Hz, 1H),
7.15 (d, J = 7.7 Hz, 2H), 5.97ꢀ5.81 (m, 1H), 5ꢀ4.81 (m, 2H), 3.61 (d, J = 6.0 Hz, 2H), 2.49 (s,
3H). 13C NMR (75 MHz, CDCl3): δ 193.0, 142.3, 140.6, 136.9, 132.7, 131.9, 129.9, 128.7,
115.9, 36.9, 20.4. MS (ESI): 161 [M+H]+.
(((3S,5S,10bR)-10-methyl-3-phenyl-3,5,6,10b-tetrahydro-2H-oxazolo[2,3-a]isoquinolin-
5-yl)methyl)mercury(II) bromide (17). Organomercurial 17 (450 mg, 0.82 mmol) was
obtained from aldehyde 16 (160 mg, 1 mmol) as a white solid in 82% yield after column
chromatography using 10% EtOAc/hexane (v/v) as the eluent. MP: 120ꢀ122 °C. Rf: 0.2 (10%
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EtOAc/hexane, v/v). [α]D = ꢀ11.8 (c 1, CH2Cl2). IR (neat): 2927, 1731, 1636, 1454, 1255,
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1033, 754 cmꢀ1. H NMR (300 MHz, CDCl3): δ 7.46ꢀ7.24 (m, 5H), 7.15 (t, J = 6.7 Hz, 1H),
7.05 (d, J = 6.7 Hz, 1H), 6.91 (d, J = 6.7 Hz, 1H), 5.46 (s, 1H), 4.45 (t, J = 8.3 Hz, 1H), 4.31
(t, J = 7.5 Hz, 1H), 3.82ꢀ3.74 (m, 1H), 3.61 (dd, J = 8.3, 7.5 Hz, 1H), 2.94 (dd, J = 15.8, 3.7
Hz, 1H), 2.73 (dd, J = 15.8, 10.5 Hz, 1H), 2.38 (s, 3H), 2.37 (dd, J = 12.0, 4.5 Hz, 1H), 2.1
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(dd, J = 12.0, 2.2 Hz, 1H). C NMR (75 MHz, CDCl3): δ 142.7, 137.9, 133.8, 130.0, 129.7,
129.0, 128.4, 128.0, 126.7, 125.2, 89.8, 72.8, 66.9, 55.1, 40.3, 27.0, 19.4. MS (ESI): 560
[M+H]+. HRMS (ESI): m/z [M+H]+ calcd for C19H21NOBrHg 560.0512, found 560.0523.
(E)-2-(4-Hydroxybut-2-enyl)benzaldehyde (18). To a stirred solution of cisꢀ2ꢀbutenꢀ1,4ꢀ
diol (528 mg, 6 mmol) and aldehyde 1 (292 mg, 2 mmol) in anhydrous dichloromethane (10
mL) was added Grubbs' II generation catalyst (42 mg, 0.05 mmol). The reaction mixture was
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stirred at rt under nitrogen atmosphere for 12 h. The solvent was evaporated under reduced
pressure and the residue was purified by column chromatography using 20% EtOAc/hexanes
(v/v) as the eluent to afford the pure allylic alcohol 18 (264 mg, 1.5 mmol) as a viscous oil in
75% yield. Rf: 0.2 (20% EtOAc/hexane, v/v). IR (neat): 3378, 2922, 1729, 1692, 1573, 1403,
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1288, 1088, 974, 763 cmꢀ1. H NMR (300 MHz, CDCl3): δ 10.16 (s, 1H), 7.77 (dd, J = 7.5,
1.1 Hz, 1H), 7.46 (td, J = 7.5, 1.3 Hz, 1H), 7.34 (td, J = 7.5, 1.1 Hz, 1H), 7.22 (dd, J = 7.5,
1.3 Hz, 1H), 5.9ꢀ5.78 (m, 1H), 5.6ꢀ5.48 (m, 1H), 4.03 (d, J = 5.6 Hz, 2H), 3.75 (d, J = 6.0
Hz, 2H). 13C NMR (75 MHz, CDCl3): δ 192.5, 142.2, 133.9, 133.6, 131.9, 131.0, 130.8,
130.5, 126.8, 63.1, 35.0. MS (ESI): 199 [M+Na]+. HRMS (ESI): m/z [M+Na]+ calcd for
C11H12O2Na 199.0734, found 199.0739.
(E)-2-(4-(tert-Butyldimethylsilyloxy)but-2-enyl)benzaldehyde (19). To a solution of
alcohol 18 (265 mg, 1.5 mmol) in dry CH2Cl2 (10 mL) was added imidazole (204 mg, 3
mmol) and TBSCl (226 mg, 1.5 mmol) under N2 atmosphere at 0 °C. The reaction mixture
was allowed to gradually warm to rt over a period of 1 h. Water was added to the reaction
mixture, the two layers were separated and the aq layer was extracted with CH2Cl2 (3x10
mL). The combined organic layers were dried over anhydrous Na2SO4 and concentrated to
give a crude residue which upon silica gel chromatography using 10% EtOAc/hexane (v/v) as
the eluent afforded pure TBS ether 23 (377 mg, 1.3 mmol) as a viscous oil in 90% yield. Rf:
0.2 (10% EtOAc/hexane, v/v). IR (neat): 2954, 2730, 1698, 1464, 1253, 1046, 837, 776 cmꢀ1.
1H NMR (300 MHz, CDCl3): δ 10.42 (s, 1H), 8.01 (d, J = 7.5 Hz, 1H), 7.69 (t, J = 7.5 Hz
,1H), 7.55 (t, J = 7.5 Hz, 1H), 7.45 (d, J = 7.5 Hz, 1H), 6.1ꢀ5.97 (m, 1H), 5.73ꢀ 5.62 (m, 1H),
4.29 (t, J = 5.0, 1.3 Hz, 2H), 3.97 (d, J = 6.2 Hz, 2H), 1.04 (s, 9H), 0.2 (s, 6H). 13C NMR (75
MHz, CDCl3): 192.2, 142.6, 133.9, 133.7, 131.39, 131.3, 130.9, 128.8, 126.7, 63.5, 34.9,
25.8, 18.3, ꢀ3.6, ꢀ5.2. MS (ESI): 313 [M+Na]+. HRMS (ESI): m/z [M+Na]+ calcd for
C17H26O2NaSi 313.1599, found 313.1607.
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((S)-2-(tert-Butyldimethylsilyloxy)-1-((3S,5S,10bR)-3-phenyl-3,5,6,10b-tetrahydro-2H-
oxazolo[2,3-a]isoquinolin-5-yl)ethyl)mercury(II) bromide (20). Organomercurial 20 (580
mg, 0.85 mmol) was obtained from aldehyde 19 (160 mg, 1 mmol) in 85% yield as a white
solid after column chromatography using 5% EtOAc/hexane (v/v) as the eluent. MP: 120ꢀ122
°C. Rf: 0.2 (5% EtOAc/hexane, v/v). [α]D25 = ꢀ3.2 (c 1, CH2Cl2). IR (neat): 2928, 2858, 1387,
1032, 961, 776 cmꢀ1. 1H NMR (300 MHz, CDCl3): δ 7.6ꢀ7.14 (m, 9H), 5.72 (s, 1H), 4.53 (dd,
J = 8.0, 7.3 Hz, 1H), 4.24 (t, J = 8.0 Hz, 1H), 4.02ꢀ3.85 (m, 2H), 3.79ꢀ3.62 (m, 2H), 3.3 (dd, J
= 15.4, 2.9 Hz, 1H), 3.18ꢀ3.06 (m, 1H), 2.75 (dd, J = 15.4, 10.2 Hz, 1H), 0.98 (s, 9H), 0.15 (s,
3H), 0.12 (s, 3H). 13C NMR (75 MHz, CDCl3): δ 142.8, 133.4, 132.4, 129.6, 128.4, 127.9,
127.5, 127.4, 127.0, 126.9, 90.7, 73.7, 68.6, 68.5, 62.5, 59.9, 37.4, 25.8, 18.0, ꢀ5.2, ꢀ5.3. MS
(ESI): 690 [M+H]+. HRMS (ESI): m/z [M+H]+ calc for C25H35NO2SiBrHg 690.1326, found
690.1320.
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(((3S,5S,6R,7aR)-3,6-diphenylhexahydropyrrolo[2,1-b]oxazol-5-yl)methyl)mercury(II)
bromide (22). Organomercurials 22 and 23 were obtained in equimolar amounts from
aldehyde 21 (160 mg, 1 mmol) in 85% yield as white solids after column chromatography
using 10% EtOAc/hexane (v/v) as the eluent.
MP: 137ꢀ139 °C. Rf: 0.3 (10% EtOAc/hexane). [α]D25 = +11.5 (c 1, CH2Cl2). IR (neat): 2923,
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2814, 1486, 1377, 1144, 1024, 901, 696 cmꢀ1. H NMR (300 MHz, CDCl3): δ 7.33ꢀ7.14 (m,
10H), 5.1 (dd, J = 5.8, 3.7 Hz, 1H), 4.47 (dd, J = 8.8, 7.5 Hz, 1H), 4.04 (t, J =7.5 Hz, 1H),
3.56 (dd, J = 8.8, 7.5 Hz, 1H), 3.5ꢀ3.43 (m, 1H), 2.9ꢀ2.76 (m, 1H), 2.66ꢀ2.55 (m, 1H), 2.13ꢀ
1.18 (m, 3H). 13C NMR (75 MHz, CDCl3): δ 142.1, 139.6, 129.2, 129.0, 127.8, 127.7, 127.6,
126.6, 97.3, 75.8, 72.4, 67.8, 55.7, 39.2, 38.6. MS (ESI): 560 [M+H]+. HRMS (ESI): m/z
[M+H]+ calcd for C19H21BrNOHg 560.0512, found 560.0501.
(((3S,5R,6S,7aR)-3,6-diphenylhexahydropyrrolo[2,1-b]oxazol-5-yl)methyl)mercury(II)
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bromide (23). MP: 135ꢀ137 °C. Rf: 0.2 (10% EtOAc/hexane). [α]D = ꢀ41.2 (c 1, CH2Cl2).
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IR (neat): 2924, 2854, 1777, 1452, 1029, 755 cmꢀ1. H NMR (300 MHz, CDCl3): δ 7.46ꢀ7.1
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(m, 10H), 5.46 (dd, J = 5.8, 3.7 Hz, 1H), 4.54 (dd, J = 8.4, 7.3 Hz, 1H), 4.08 (dd, J =7.7, 7.3
Hz, 1H), 3.99 (t, J = 5.9 Hz, 1H), 3.65 (t, J =8.4 Hz, 1H), 3.53 (t, J =7.7 Hz, 1H), 2.58ꢀ2.53
(m, 1H), 2.49ꢀ2.43 (m, 1H), 2.05ꢀ1.91 (m, 1H), 1.7ꢀ1.55 (m, 1H). 13C NMR (75 MHz,
CDCl3): δ 141.9, 140.7, 129.5, 129.1, 128.4, 128.1, 127.6, 126.5, 99.1, 75.6, 67.9, 67.7, 50.8,
36.8, 31.8. MS (ESI): 560 [M+H]+. HRMS (ESI): m/z [M+H]+ calcd for C19H21NOBrHg
560.0512, found 560.0500.
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General procedure for demercuration:
To a stirred solution of organomercurial (1 eq) in dry toluene (0.25 M) cooled at –78 oC was
added a solution of tributyltin hydride (1 eq) in toluene (0.25 M) followed by triethylborane
o
(0.6 eq). The reaction mixture was stirred at –78 C for 30 min, diluted with EtOAc (0.1 M)
and saturated aq KF (0.5 M). The reaction mixture was stirred for another 30 min at rt. The
precipitated tributyltin fluoride was removed by filtration and the solid washed with EtOAc.
The combined filtrates were washed with brine, dried over anhydrous Na2SO4 and
concentrated in vacuo. The residual oil was purified by column chromatography using
EtOAc/hexane (v/v) as the eluent to afford pure demercuration product.
(3S,5R,10bR)-5-Methyl-3-phenyl-3,5,6,10b-tetrahydro-2H-oxazolo[2,3-a]isoquinoline
(5). Following the general procedure for demercuration, compound 5 (210 mg, 0.8 mmol)
was prepared from organomercurial 4 (545 mg, 1 mmol) as a colorless liquid in 80% yield
after column chromatography using 10% EtOAc/hexane (v/v) as the eluent. Rf: 0.2 (10%
EtOAc/hexane, v/v). [α]D25 = +40 (c 1, CHCl3). IR (neat): 2927, 2854, 1730, 1456, 1276, 952,
747 cmꢀ1. 1H NMR (CDCl3, 300 MHz): δ 7.42ꢀ7.0 (m, 9H), 5.41 (s, 1H), 4.38ꢀ4.28 (m, 2H),
3.65ꢀ3.55 (m, 1H), 3ꢀ2.88 (m, 1H), 2.76ꢀ2.59 (m, 2H), 1.08 (d, J = 6.0 Hz, 3H). 13C NMR (75
MHz, CDCl3): δ 142.7, 134.9, 132.6, 128.4, 127.9, 127.8, 127.4, 126.9, 126.5, 126.2, 90.5,
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71.8, 66.3, 50.5, 37.3, 21.2. MS (ESI): 266 [M+H]+. HRMS (ESI): m/z [M+H]+ calcd for
C18H20NO 266.1539, found 266.1536.
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(S)-2-((R)-3-Methyl-3,4-dihydroisoquinolin-2(1H)-yl)-2-phenylethanol (9). Following the
general procedure for demercuration, compound 9 (240 mg, 0.9 mmol) was prepared from
organomercurial 4 (545 mg, 1 mmol) using excess tributyltin hydride (0.5 mL, 2 mmol) as a
colorless liquid in 90% yield after column chromatography using 20% EtOAc/hexane (v/v) as
the eluent. Rf: 0.2 (20% EtOAc /hexane). [α]D25 = +10.4 (c 1, CHCl3). IR (neat): 2957, 2863,
1457, 1219, 1075, 701 cmꢀ1. 1H NMR (CDCl3, 300 MHz): δ 7.42ꢀ6.88 (m, 9H), 3.89 (dd, J =
9.6, 5.7 Hz, 1H), 3.84 (dd, J = 11.4, 5.7 Hz, 1H), 3.81ꢀ3.63 (m, 3H), 3.55 (t, J = 5.7 Hz, 1H),
3.21 (dd, J = 15.4, 4.8 Hz, 1H), 3.17ꢀ2.97 (bs, 1H), 2.47 (d, J =15.4 Hz, 1H), 0.99 (d, J=6.7
Hz, 3H). 13C NMR (75 MHz, CDCl3): δ 139.1, 133.7, 133.1, 129.3, 128.7, 128.4, 127.8,
126.3, 126.1, 125.4, 68.0, 62.3, 50.5, 45.3, 35.6, 13.1. MS (ESI): 268 [M+H]+. HRMS (ESI):
m/z [M+H]+ calcd for C18H22NO 268.1695, found 268.1694.
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(3S,5R,10bR)-5,10b-Dimethyl-3-phenyl-3,5,6,10b-tetrahydro-2H-oxazolo[2,3-
a]isoquinoline (26). To a solution of compound 24 (160 mg, 1 mmol) and (S)ꢀphenyl
glycinol (151 mg, 1.1 mmol) in anhydrous dichloromethane (1 mL) was added Ti(OEt)4 (0.5
mL, 2.2 mmol) and the mixture stirred at rt for 16 h to ensure imine formation. The reaction
mixture was diluted with anhydrous dichloromethane (4 mL). Organomercurial 25 (420 mg,
0.75 mmol) was obtained following the general procedure in 75% yield after flash column
chromatography using 10% EtOAc/hexane (v/v) as the eluent. Rf: 0.2 (10% EtOAc/hexane,
v/v). Since it was found to be unstable, it was taken to next step without characterization.
Following the general procedure for demercuration, compound 26 (140 mg, 0.5 mmol) was
obtained from organomercurial 25 (420 mg, 0.75 mmol) as a colorless liquid in 70% yield
after column chromatography using 10% EtOAc/hexane (v/v) as the eluent. Rf: 0.2 (10%
25
EtOAc/hexane). [α]D = +16.4 (c 1, CHCl3). IR (neat): 2925, 2866, 1755, 1455, 1251, 1073,
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759 cmꢀ1. H NMR (300 MHz, CDCl3): δ 7.5ꢀ7.0 (m, 9H), 4.17 (dd J = 7.5, 3.7 Hz, 1H), 3.78
(t, J = 7.5 Hz, 1H), 3.65ꢀ3.5 (m, 2H), 2.94 (dd, J = 16.6, 11.3 Hz, 1H), 2.49 (dd, J = 16.6, 3.7
Hz, 1H), 1.76 (s, 3H), 1.36 (d, J = 6.7 Hz, 3H). 13C NMR (75 MHz, CDCl3): δ 146.4, 139.3,
135.3, 128.2, 128.1, 127.2, 126.9, 126.5, 95.9, 72.7, 58.6, 48.7, 29.9, 28.2, 21.6. MS (ESI):
280 [M+H]+. HRMS (ESI): m/z [M+H]+ calcd for C19H22NO 280.1695, found 280.1690.
(S)-2-((1S,3R)-5-(Benzyloxy)-6-methoxy-1,3-dimethyl-3,4-dihydroisoquinolin-2(1H)-yl)-
2-phenylethanol (30). Following the procedure detailed above, ketone 28 (296 mg, 1 mmol)
was subjected to aminomercurationꢀdemercuration sequence to furnish compound 30 (332
mg, 0.8 mmol) in 80% yield after column chromatography using 10% EtOAc/hexane (v/v) as
the eluent. Rf: 0.3 (10% EtOAc/hexane). [α]D25 = +42.7 (c 1, CH2Cl2). IR (neat): 2924, 2854,
1717, 1590, 1455, 1251, 1073, 759 cmꢀ1. 1H NMR (CDCl3, 300 MHz): δ 7.49ꢀ7.17 (m, 10H),
6.91ꢀ6.86 (m, 2H), 5.02ꢀ4.97 (m, 2H), 3.98 (dd, J = 8.0, 3.7 Hz, 1H), 3.89 (s, 3H), 3.69 (t, J =
8.0 Hz, 1H), 3.55 (dd, J = 8.1, 3.7 Hz, 1H), 2.88 (dd, J = 15.7, 3.4 Hz, 1H), 2.65ꢀ2.59 (m,
1H), 2.21 (dd, J = 15.7, 9.6 Hz, 1H), 1.76 (s, 3H), 0.86 (d, J = 6.8 Hz, 3H). 13C NMR (75
MHz, CDCl3): δ 151.3, 146.5, 143.2, 137.8, 128.54, 128.5, 128.3, 128.2, 128.1, 127.9, 126.8,
110.7, 95.7, 74.0, 72.5, 68.3, 58.4, 48.3, 31.7, 29.4, 21.7. MS (ESI): 416 [M+H]+. HRMS
(ESI): m/z [M+Na]+ calcd for C27H29NNaO3 438.2040, found 438.2050.
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(3S,5R,10bR)-5,10-Dimethyl-3-phenyl-3,5,6,10b-tetrahydro-2H-oxazolo[2,3-
a]isoquinoline (32). Following the general procedure for demercuration, compound 32 (210
mg, 0.8 mmol) was prepared from organomercurial 17 (559 mg, 1 mmol) as a colorless liquid
in 80% yield after column chromatography using 10% EtOAc/hexane (v/v) as the eluent. Rf:
0.2 (10% EtOAc/hexane). [α]D25 = +58.9 (c 1, CH2Cl2). IR (neat): 2926, 2853, 1597, 1379,
1037, 700 cmꢀ1. 1H NMR (CDCl3, 300 MHz): δ 7.49ꢀ6.87 (m, 8H), 5.31 (s, 1H), 4.6ꢀ 4.41 (m,
2H), 3.7ꢀ3.63 (m, 1H), 3.11ꢀ2.99 (m, 1H), 2.85ꢀ2.67 (m, 2H), 2.35 (s, 3H), 1.2 (d, J = 6.0 Hz,
3H). 13C NMR (75 MHz, CDCl3): δ 143.0, 137.7, 135.1, 130.2, 128.5, 128.4, 128.0, 126.9,
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126.5, 125.3, 89.1, 70.8, 64.8, 49.3, 38.0, 21.0, 19.0. MS (ESI): 280 [M+H]+. HRMS (ESI):
m/z [M+H]+ calcd for C19H22NO 280.1691, found 280.1701.
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(3S,5S,10bR)-3-Phenyl-5-((2,2,6,6-tetramethylpiperidin-1-yloxy)methyl)-3,5,6,10b-
tetrahydro-2H-oxazolo[2,3-a]isoquinoline (10). To a stirred solution of organomercurial 4
(545 mg, 1 mmol) in anhydrous DMF (10 mL) was added TEMPO (450 mg, 3 mmol). This
solution was then added dropwise via canula to an oxygen saturated solution of NaBH4 (150
mg, 4 mmol) in dry DMF (4 mL) cooled at 0 oC. After 10 min, the precipitated mercury was
filtered through Celite and the solution was diluted with ether. The organic phase was washed
with water, brine, dried over Na2SO4 and concentrated. The crude residue was purified by
column chromatography using 5% EtOAc/hexane as the eluent to afford pure 10 (335 mg, 0.8
mmol) as a colorless liquid in 80 % yield. Rf: 0.5 (10% EtOAc/hexane). [α]D25 = +24.5 (c 1,
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CHCl3). IR (neat): 2925, 2854, 1459, 1049, 956, 746 cmꢀ1. H NMR (300 MHz, CDCl3): δ
7.42ꢀ7.08 (m, 9H), 5.46 (s, 1H), 4.55 (t, J = 7.5 Hz, 1H), 4.32 (dd, J = 7.7, 7.5 Hz, 1H), 3.88ꢀ
3.8 (m, 1H), 3.68ꢀ3.56 (m, 2H), 3.17ꢀ3.07 (m, 1H), 2.96 (dd, J = 16.0, 3.5 Hz, 1H), 2.69 (dd,
J = 16.0, 9.0 Hz,1H), 1.6ꢀ0.8 (m, 18H). 13C NMR (75 MHz, CDCl3): δ 141.7, 134.2, 132.7,
128.2, 127.8, 127.7, 127.5, 126.8, 126.4, 126.1, 89.9, 80.2, 71.6, 66.2, 59.4, 54.3, 39.2, 32.5,
31,7, 29.4, 19.9, 19.8, 16.7. MS (ESI): 421 [M+H]+. HRMS (ESI): m/z [M+H]+ calcd for
C27H37N2O2 421.2858, found 421.2855.
(S)-(1,2,3,4-Tetrahydroisoquinolin-3-yl)methanol (11). To a stirred solution of 10 (335
mg, 0. 8 mmol) in 50% aq CH3COOH (8 mL) was added activated Zn dust (565 mg, 8.7
mmol). The mixture was submerged in an oil bath maintained at 100 °C and heated for 1 h.
After cooling to rt, the mixture was diluted with H2O (8 mL) and extracted with Et2O (3x5
mL). The combined extracts were neutralized with saturated aq sodium bicarbonate solution,
dried over Na2SO4 and evaporated. The residue was purified by column chromatography
using 20% EtOAc/hexane (v/v) as the eluent to afford the compound 11 (170 mg, 0.6 mmol)
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as a colorless liquid in 75 % yield. Rf: 0.2 (10% EtOAc/hexane). [α]D25 = +56.8 (c 1, CHCl3).
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(dd, J = 16.2, 11.5 Hz, 1H), 2.63 (dd, J = 16.2, 2.4 Hz, 1H). 13C NMR (75 MHz, CDCl3) : δ
134.3, 132.4, 128.9, 126.4, 125.9, 124.1, 75.3, 68.0, 65.5, 29.4. MS (ESI): 164 [M+H]+.
(S)-2-((1R,3R)-1,3-Dimethyl-3,4-dihydroisoquinolin-2(1H)-yl)-2-phenylethanol (6). To a
stirred solution of compound 5 (265 mg, 1 mmol) in dry ether (4 mL) cooled at 0 °C was
added methyl magnesium iodide (1.5 mL, 1.5 mmol, 1M in ether) dropwise under N2
atmosphere. Stirring was continued for 1 h at 0 °C, the reaction was quenched with saturated
aq NH4Cl. The organic layer was separated from the aq layer and the aq layer was extracted
with ether (2x5 mL). The combined organic layers were washed with saturated brine, dried
over anhydrous Na2SO4 and evaporated. The crude product was purified by column
chromatography using 10% EtOAc/hexane (v/v) as the eluent to afford the pure product 6
(220 mg, 0.8 mmol) in 80 % yield as a colorless liquid. Rf: 0.3 (10% EtOAc/hexane, v/v).
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[α]D = +46.9 (c 4, CHCl3). IR (neat): 2923, 2854, 1739, 1376, 1032, 701 cmꢀ1. H NMR
(300 MHz, CDCl3): δ 7.0 (d, J = 6.4 Hz, 2H), 6.92ꢀ6.75 (m, 6H), 6.55 (d, J = 7.3 Hz, 1H), 4.4
(dd, J = 13.5, 6.7 Hz, 1H), 4.17 (dd, J = 9.8, 5.6 Hz, 1H), 3.86 (t, J = 9.8 Hz, 1H), 3.72ꢀ3.6
(m, 1H), 3.5ꢀ3.4 (m, 1H), 2.48ꢀ2.2 (m, 2H), 1.48 (d, J = 6.4 Hz, 3H), 1.4 (d, J = 5.6 Hz, 3H).
13C NMR (75 MHz, CDCl3): δ 139.0, 138.5, 134.0, 128.9, 128.2, 127.5, 127.0, 126.8, 126.3,
125.4, 61.4, 60.3, 51.5, 47.3, 33.4, 24.5, 19.7. MS (ESI): 282 [M+H]+. HRMS (ESI): m/z
[M+H]+ calcd for C19H24NO 282.1852, found 282.1851.
(S)-2-((1R,3R)-3-Methyl-1-vinyl-3,4-dihydroisoquinolin-2(1H)-yl)-2-phenylethanol (7).
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To a stirred solution of compound 5 (265 mg, 1 mmol) in dry THF (5 mL) cooled at –78 C
was added vinyl magnesium bromide (1.5 mL, 1.5 mmol, 1M in THF) dropwise under N2
atmosphere and gradually allowed to warm to 0 °C over a period of 1 h. The reaction was
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quenched with saturated aq NH4Cl and the aq layer extracted with ethyl acetate (2x5 mL).
The combined organic layers were washed with saturated brine, dried over anhydrous
Na2SO4 and the solvent was removed in vacuo to afford pure 7 (220 mg, 0.75 mmol) as a
colorless liquid in 75% yield after column chromatography using 5% EtOAc/hexane (v/v) as
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the eluent. Rf: 0.5 (10% EtOAc/hexane, v/v). [α]D = +35.3 (c 1, CHCl3). IR (neat): 2922,
2852, 1637, 1460, 1374, 1036, 757 cmꢀ1. H NMR (300 MHz, CDCl3): δ 7.5ꢀ6.6 (m, 9H),
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6.03ꢀ5.88 (m, 1H), 5.15ꢀ4.85 (m, 2H), 4.73ꢀ4.70 (m, 1H), 4.23ꢀ4.2 (m, 1H), 3.89 (t, J = 8.7
Hz, 1H), 3.6ꢀ3.48 (m, 2H), 2.5ꢀ2.3 (m, 2H), 1.28 (d, J = 5.1 Hz, 3H). 13C NMR (75 MHz,
CDCl3): δ 141.6, 137.4, 134.9, 129.9, 128.77, 128.71, 127.8, 127.7, 127.4, 125.9, 125.2,
116.5, 61.6, 60.9, 58.7, 47.8, 34.3, 19.3. MS (ESI): 294 [M+H]+. HRMS (ESI): m/z [M+H]+
calcd for C20H24NO 294.1853, found 294.1857.
(S)-2-((1R,3R)-3-Methyl-1-(oct-1-ynyl)-3,4-dihydroisoquinolin-2(1H)-yl)-2-
phenylethanol (8). To a stirred solution of 1ꢀoctyne (330 mg, 3 mmol) in dry THF (1 mL)
was added iꢀpropylmagnesium chloride (3 mL, 3 mmol, 1M in THF) dropwise under N2
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atmosphere at –10 C. The reaction mixture was gradually allowed to warm to 0 °C and
stirred further at the same temperature for 30 min. The reaction mixture was recooled to –10
oC and compound 5 (265 mg, 1 mmol) in dry THF (4 mL) was added to it. Stirring was
continued for 1 h at 0 °C, the reaction was quenched with saturated aq NH4Cl. The layers
were separated and the aq layer extracted with ether (2x5 mL). The combined organic layers
were washed with saturated brine, dried over anhydrous Na2SO4 and the solvent was removed
in vacuo. The crude product was purified through silica gel chromatography using 5%
EtOAc/hexane (v/v) as the eluent to afford 8 (280 mg, 0.75 mmol) as a colorless liquid in
75% yield. Rf: 0.3 (10% EtOAc/hexane). [α]D25 = +54.4 (c 1, CHCl3). IR (neat): 2927, 2860,
1601, 1455, 1157, 1036, 747 cmꢀ1. 1H NMR (300 MHz, CDCl3): δ 7.25ꢀ6.76 (m, 9H), 4.8 (s,
1H), 4.28 (dd, J = 8.1, 5.6 Hz, 1H), 4.06 (dd, J = 11.1, 8.1 Hz, 1H), 3.87 (dd, J = 11.1, 5.6
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Hz, 1H), 3.74ꢀ3.6 (m, 1H), 2.73 (dd, J = 16.0, 4.5 Hz, 1H), 2.39 (dd, J = 16.0, 8.3 Hz, 1H),
2.14 (t, J = 6.8 Hz, 2H), 1.5ꢀ0.77 (m, 14H). 13C NMR (75 MHz, CDCl3): δ 139.6, 136.5,
134.2, 128.4, 128.0, 127.1, 126.5, 126.3, 125.6, 86.0, 80.7, 62.47, 62.4, 49.3, 49.2, 36.2, 31.2,
28.5, 22.4, 20.4, 18.8, 13.9, 13.5. MS (ESI): 376 [M+H]+. HRMS (ESI): m/z [M]+ calcd for
C26H33NO 375.2524, found 375.2556.
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(S)-2-((1R,3R)-1,3-dimethyl-3,4-dihydroisoquinolin-2(1H)-yl)-2-phenylethanol (6). To a
stirred solution of compound 26 (279 mg, 1 mmol) in anhydrous THF (4 mL) cooled at 0 °C
was added sodium borohydride (185 mg, 5 mmol) followed by trifluoroacetic acid (0.8 mL,
10 mmol) under N2 atmosphere and the mixture allowed to attain rt gradually over a period of
30 min. The reaction was quenched with aq NaHCO3. The organic layer was separated from
aq layer and the aq layer was extracted with ether (2x5 mL). The combined organic layers
were washed with brine, dried over anhydrous Na2SO4 and the solvent was removed in
vacuo. The crude product was purified through silica gel chromatography using 10%
EtOAc/petroleum ether (v/v) to afford 1,3ꢀanti alcohol 6 (168 mg, 0.6 mmol) in 60% yield.
(S)-2-((1S,3R)-1,3-Dimethyl-3,4-dihydroisoquinolin-2(1H)-yl)-2-phenylethanol (27). To a
suspension of LiAlH4 (410 mg, 10.3 mmol) in anhydrous ether (10 mL) cooled at ꢀ10 °C was
added a solution of anhydrous AlCl3 (500 mg, 3.5 mmol) dissolved in anhydrous ether (10
mL) under argon atmosphere and the mixture stirred for 15 min. To the resulting alane, a
solution of compound 26 (279 mg, 1 mmol) in dry THF (5 mL) was slowly added. The
reaction mixture was stirred for another 30 min at ꢀ10 °C and quenched by adding small ice
pieces. The precipitated solids were filtered through Celite and the solids were washed with
hot EtOAc (2x5 mL). The combined filtrates were evaporated under reduced pressure and the
residue was purified by column chromatography using 10% EtOAc/hexane (v/v) as the eluent
to afford pure 1,3ꢀsyn alcohol 27 (210 mg, 0.75 mmol) as a viscous liquid in 75% yield. Rf:
0.3 (10% EtOAc/hexane, v/v). [α]D25 = +121 (c 1, CHCl3). IR (neat): 2960, 2925, 1453, 1374,
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1031, 758 cmꢀ1. 1H NMR (300 MHz, CDCl3) : δ 7.36ꢀ7.03 (m, 9H), 4.35 (dd, J = 9.7, 5.1 Hz,
1H), 4.33ꢀ4.28 (m, 1H), 4.1 (dd, J = 10.5, 9.7 Hz, 1H), 3.6 (dd, J = 10.5, 5.1 Hz, 1H), 3.65ꢀ
3.58 (m, 1H), 3.05 (dd, J = 15.1, 4.5 Hz, 1H), 2.5 (dd, J = 15.5, 4.5 Hz, 1H), 1.51 (d, J = 6.4
Hz , 3H), 0.49 (d, J = 6.4 Hz, 3H). 13C NMR (75 MHz, CDCl3): δ 140.8, 139.6, 133.9, 128.5,
128.3, 127.7, 126.4, 125.8, 125.6, 60.2, 51.2, 44.8, 38.1, 23.0, 15.7. MS (ESI): 282 [M+H]+.
HRMS (ESI): m/z [M+H]+ calcd for C19H24NO 282.1852, found 282.1846.
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(S)-2-((1S,3R)-5-(benzyloxy)-6-methoxy-1,3-dimethyl-3,4-dihydroisoquinolin-2(1H)-yl)-
2-phenylethanol (31). Following the procedure detailed above, compound 30 (332 mg, 0.8
mmol) was subjected to alane reduction to furnish compound 31 ( 250 mg, 0.6 mmol) in 75%
yield after column chromatography using 20% EtOAc/hexane (v/v) as the eluent. Rf: 0.2
(20% EtOAc/hexane). [α]D25 = +86.7 (c 1, CH2Cl2). IR (neat): 2958, 2924, 2854, 1717, 1590,
1455, 1351, 1030, 759 cmꢀ1. 1H NMR (CDCl3, 300 MHz): δ 7.49ꢀ7.27 (m, 10H), 6.9ꢀ6.78 (m,
2H) 5.1ꢀ4.93 (m, 2H), 4.28 (dd, J = 10.5, 5.1 Hz, 1H), 4.24ꢀ4.17 (m, 1H), 4.03 (t, J = 10.1
Hz, 1H), 3.87 (s, 3H), 3.63 (dd, J = 10.5, 5.1 Hz, 1H), 3.54ꢀ3.46 (m, 1H), 2.7 (dd, J = 16.3,
4.7 Hz, 1H), 2.56 (dd, J = 16.3, 4.8 Hz, 1H), 1.46 (d, J = 6.4 Hz, 3H), 0.4 (d, J = 6.5 Hz, 3H).
13C NMR (75 MHz, CDCl3): δ 150.4, 145.3, 139.6, 134.2, 128.5, 128.3, 127.92, 127.9, 127.6,
121.9, 110.1, 74.2, 60.2, 60.1, 55.8, 50.6, 44.3, 32.3, 23.1. MS (ESI): 418 [M+H]+. HRMS
(ESI): m/z [M+Na]+ calcd for C27H31NNaO3 440.2196, found 440.2218.
(3S,5R,10bR)-5,10-dimethyl-3-phenyl-3,5,6,10b-tetrahydro-2H-oxazolo[2,3-
a]isoquinoline (32). To a stirred solution of compound 16 (160 mg, 1 mmol) and (S)ꢀphenyl
glycinol (151 mg, 1.1 mmol) in 1,4ꢀdioxane (5 mL) were added DPEphos (8 mg, 3 mol%)
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and [Rh(COD)2]BF4 (10 mg, 2.5 mol%) under N2 atmosphere and heated at 110 C for 16 h.
The reaction mixture was allowed to cool to rt and filtered through Celite. The residue was
washed with EtOAc (2x5 mL) and the combined filtrate washed successively with water,
brine, dried over anhydrous Na2SO4 and concentrated. The crude product was purified by
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silica gel chromatography using 10% EtOAc/petroleum ether (v/v) to give pure compound 32
(200 mg, 0.7 mmol) as a colorless liquid in 70% yield.
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(3S,5R,10bR)-7-(benzyloxy)-8-methoxy-5-methyl-3-phenyl-3,5,6,10b-tetrahydro-2H-
oxazolo[2,3-a]isoquinoline (33). Following the procedure detailed above, aldehyde 12 ( 282
mg, 1 mmol) was subjected to catalytic hydroamination to furnish compound 33 ( 340 mg,
0.85 mmol) in 85% yield after column chromatography using 20% EtOAc/hexane (v/v) as the
eluent. Rf: 0.2 (20% EtOAc/hexane). [α]D25 = +79.5 (c 1, CH2Cl2). IR (neat): 2926, 2850,
1590, 1405, 1053, 752 cmꢀ1. 1H NMR (CDCl3, 300 MHz): δ 7.48ꢀ7.24 (m, 10H), 7.17 (d, J =
8.5 Hz, 1H), 6.9 (d, J = 8.5 Hz, 1H), 5.45 (s, 1H), 5.01 (d, J = 11.1 Hz, 1H), 4.97 (d, J = 11.1
Hz, 1H), 4.44ꢀ4.37 (m, 2H), 3.9 (s, 3H), 3.69 (dd, J = 11.1, 10.6 Hz, 1H), 2.94 (dd, J = 16.3,
3.2 Hz, 1H), 2.91ꢀ2.82 (m, 1H), 2.4 (dd, J = 16.3, 10.0 Hz, 1H), 1.11 (d, J = 6.1 Hz, 3H). 13C
NMR (75 MHz, CDCl3): δ 152.1, 144.0, 142.8, 137.7, 132.4, 131.9, 130.8, 128.7, 128.6,
128.4, 128.3, 127.9, 127.5, 126.6, 126.4, 123.8, 110.7, 90.3, 74.5, 71.6, 66.1, 55.8, 50.1,
31.4, 21.3. MS (ESI): 402 [M+H]+. HRMS (ESI): m/z [M+H]+ calcd for C26H28NO3
402.2064, found 402.2086.
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Acknowledgements
P.S. is thankful to CSIR for SRF fellowship. S.R. acknowledges funding from DST
(SR/S1/OCꢀ5/2011) and CSIR, New Delhi as a part of the XII five year plan programme
under the title ORIGIN (CSCꢀ108).
1
Supporting Information: H and 13C NMR of new compounds is available on the WWW
under http://www.pubs.acs.org/or from the author.
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