Enantiospecific Stereodivergent Synthesis of trans- and cis-N(2), 3-Dimethyl- 4-phenyl-1, 2, 3, 4-tetrahydroisoquinolines

Article abstract of DOI:10.1002/asia.200900470

The acid-promoted cyclizations of a range of N-benzylethanolamines (derived from pseudoephedrine or ephedrine) give the corresponding trans-N(2), 3-dimethyl-4-phenyl-1, 2, 3, 4- tetrahydroisoquinolines with high levels of diastereoselectivity and in good yields of isolated product. The cyclizations of the corresponding chromium tricarbonyl complexes are rendered completely stereoselective. Acidpromoted cyclization of N-(3′, 4′- dimethoxybenzyl) ephedrine and its chromium tricarbonyl complex occur with complementary diastereoselectivities to give trans- and cis-N(2), 3-dimethyl-4- phenyl-6, 7-dimethoxy-1, 2, 3, 4-tetrahydro- isoquinoline, respectively, in >99:1 d.r. The latter is consistent with a "double inversion" mechanism, which involves neighboring group participation by the chromium tricarbonyl moiety followed by rearomatization to give the corresponding cis-tetrahydroisoquinoline with overall retention of configuration.

Full text of DOI:10.1002/asia.200900470

DOI: 10.1002/asia.200900470
Enantiospecific Stereodivergent Synthesis of trans- and cis-N(2),3-Dimethyl-
4-phenyl-1,2,3,4-tetrahydroisoquinolines
Steven J. Coote, Stephen G. Davies,* Ai M. Fletcher, Paul M. Roberts, and
James E. Thomson[a]
Dedicated to the 150th anniversary of Japan–UK diplomatic relations
Abstract: The acid-promoted cycliza-
tions of a range of N-benzylethanola-
mines (derived from pseudoephedrine
or ephedrine) give the corresponding
trans-N(2),3-dimethyl-4-phenyl-1,2,3,4-
promoted cyclization of N-(3’,4’-dime-
thoxybenzyl)ephedrine and its chromi-
um tricarbonyl complex occur with
complementary diastereoselectivities to
give trans- and cis-N(2),3-dimethyl-4-
phenyl-6,7-dimethoxy-1,2,3,4-tetrahy-
dro-isoquinoline,
>99:1 d.r. The latter is consistent with
“double inversion” mechanism,
which involves neighboring group par-
ticipation by the chromium tricarbonyl
moiety followed by rearomatization to
give the corresponding cis-tetrahydroi-
soquinoline with overall retention of
configuration.
respectively,
in
a
tetrahydroisoquinolines
with
high
levels of diastereoselectivity and in
good yields of isolated product. The
cyclizations of the corresponding chro-
mium tricarbonyl complexes are ren-
dered completely stereoselective. Acid-
Keywords: chromium · cyclization ·
ephedrine
·
pseudoephedrine
·
tetrahydroisoquinoline
Introduction
from the same acyclic precursor 2 (Figure 1). In general,
therefore, a biomimetic[7] synthetic route for the construc-
tion of 4-aryltetrahydroisoquinolines is the cyclization of an
appropriately substituted N-benzyl-1-arylethanolamine;[8]
for instance, the acid-promoted cyclization of N-benzyl-1-
4-Aryl-1,2,3,4-tetrahydroisoquinolines[1] are widespread in
nature and display potent pharmacological activity. For ex-
ample, nomifensine 1 is a powerful inhibitor of the uptake
of monamine neurotransmitters and has been marketed as a
drug under the trade name Merital for the treatment of de-
pression.[2] More importantly, this compound displays enan-
tioselective pharmacological activity, with the (S)-enantio-
mer being the eutomer.[3] As a result of the biological signif-
icance of 4-aryltetrahydroisoquinolines, there has been
much interest in their synthesis.[3,4] Biogenetically it is
thought that tetrahydroisoquinoline alkaloids are derived
from acyclic precursors. For example, the alkaloids (S)-lati-
fine 3[5] and (S)-cherylline 4[6] are believed to be derived
[a] Dr. S. J. Coote, Prof. S. G. Davies, Dr. A. M. Fletcher,
Dr. P. M. Roberts, Dr. J. E. Thomson
Department of Chemistry
Chemistry Research Laboratory
University of Oxford
Mansfield Road, Oxford, OX1 3TA (UK)
Fax : (+44)1865-275633
E-mail: steve.davies@chem.ox.ac.uk
Figure 1. Biologically active tetrahydroisoquinolines (S)-nomifensine 1,
(S)-latifine 3 and (S)-cherylline 4.
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phenylethanolamine 5 is known to give the corresponding 4-
phenyltetrahydroisoquinoline 6 in good yield (Scheme 1).[9]
Scheme 1. Reagents and conditions: a) TFA/H2SO4 (1:1), CH2Cl2, reflux,
30 min.
This synthetic strategy has been widely employed for the
preparation of 4-aryltetrahydroisoquinolines functionalized
in both aromatic rings, the ring closure being facilitated by
the presence of electron-releasing substituents on the N-
benzyl group and retarded with electron-withdrawing sub-
stituents. Despite being widely available, enantiopure N-
benzyl-1-arylethanolamines have not been previously uti-
lized for the formation of 4-aryltetrahydroisoquinolines
through an acid-catalysed cyclization procedure.[10] If the
mechanism of such a process were to proceed via a free ben-
zylic carbocation (SN1) for a substrate such as 5 (with only
one stereogenic center at the benzylic position) then all ste-
reochemical information would be lost giving rise to a race-
mic product. If, however, the N-benzyl substituent partici-
pates via an intramolecular SN2-type displacement, the ste-
reochemical integrity would be maintained giving a product
with inversion of configuration. The enantiomeric excess of
the 4-aryltetrahydroisoquinoline produced as a consequence
of the acid-promoted cyclization of an enantiopure N-
benzyl-1-arylethanolamine will reflect the relative impor-
tance of these two competing mechanistic pathways, with
any enantiomeric excess arising as a consequence of the
latter reaction manifold. As part of our ongoing research
program concerning the utility of arene chromium tricarbon-
yl complexes in synthesis,[11–14] we have previously reported
the enantiospecific synthesis of (R)-2-methyl-4-phenyl-6,7-
dimethoxytetrahydroisoquinoline 9 from (S)-1-phenyl-2-(N-
methylamino)ethanol (halostachine) derivatives 7 and 10.[13]
In the case where the substrate is complexed to a chromium
tricarbonyl moiety, the acid-mediated cyclization of 7 was
found to proceed with complete retention of configuration
to give 9 in >96% ee (after oxidative decomplexation), con-
sistent with a “double inversion” mechanism using neigh-
bouring group participation of the chromium tricarbonyl
moiety. However, in the absence of the chromium tricarbon-
yl functionality the cyclization of 10 proceeds with apprecia-
ble levels of racemization, even at low temperature
(Scheme 2).
Scheme 2. Reagents and conditions: a) HBF4·OMe2, CH2Cl2, À208C,
72 h; b) O2, Et2O, hn, 48 h; c) TFA/H2SO4 (1:1), CH2Cl2, reflux, 30 min;
d) HBF4·OMe2, CH2Cl2, À208C, 69 h. [a] The reaction only proceeded to
50% conversion.
We therefore proposed to investigate acid-promoted diaste-
reoselective cyclization reactions and also to exploit arene
chromium tricarbonyl chemistry for the control of stereo-
chemistry in the constuction of the new C(4)-stereogenic
center within the tetrahydroisoquinoline scaffold. In the
case of an N-3,4-dimethoxybenzyl substituted precursor,
such as the halostachine derivatives 7 and 10, either of the
mesomerically electron-donating methoxy substituents may
facilitate the cyclization reaction (either through an SN1 or
SN2-type mechanism): under the influence of the para-me-
thoxy group the cyclization step may proceed via a five-
membered ring spirocyclic intermediate 12, followed by di-
enone-phenol-type rearrangement to give the corresponding
six-membered ring intermediate 13, whilst the influence of
the meta-methoxy group may effect cyclization to 13 direct-
ly. Subsequent loss of a proton would give rise to the ob-
served
3,4-disubstituted
tetrahydroisoquinoline
14
(Figure 2).[18]
To probe the mechanism and substrate scope of this reac-
tion manifold we proposed to investigate the acid-mediated
To date, there appear to be few reports assessing the
levels of diastereoselectivity observed during acid-mediated
cyclization reactions of 1,2-disubstituted precursors for the
preparation
of
3-substituted-4-aryltetrahydroisoquino-
lines.[15,16] A single account of work in this area concluded
that insufficient resolution by 1H NMR spectroscopy pre-
cluded an assessment of the reaction diastereoselectivity.[17]
Figure 2. Cyclization of 11 via potential intermediates 12 and 13.
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Chem. Asian J. 2010, 5, 589 – 604

Cyclization of Substituted N-Benzylethanolamines
cyclizations of (1R,2S)-ephedrine and (1R,2R)-pseudoephe-
drine derivatives 15 and 16 and the corresponding chromium
tricarbonyl complexes 17 and 18, respectively (Figure 3).
Part of this work has been communicated previously.[14]
gave the corresponding trans-tetrahydroisoquinolones 39–43
in ꢀ93:7 d.r. (Scheme 4). The trans-configurations within
the major diastereoisomers 39–43 were established by
3
1H NMR J coupling constant analyses which showed char-
asteristic coupling constants of 8.0–8.5 Hz between the
C(3)H and C(4)H protons;[19] the minor components were
therefore assigned as the corresponding cis-diastereoisomers
1
3
44–48 which displayed diagnostic H NMR J coupling con-
stants of 4.4–4.6 Hz between the C(3)H and C(4)H protons,
although the coupling constants of these minor components
could not be determined in some cases.[19] 1H NMR NOE
difference analyses of 41 and 46 confirmed this assignment:
for trans-41 irradiation of C(4)H showed a small enhance-
ment of 4.0% to the adjacent C(3)H proton, whereas for
cis-46 irradiation of the C(4)H proton gave a much larger
enhancement of 8.5% to the C(3)H proton. Furthermore,
the relative trans-configuration within 42 was unambiguous-
ly established by X-ray crystallographic analysis, with the
(3S,4R)-absolute configuration assigned from the known
[(1R,2S)-ephedrine 19 derived] (S)-configuration of the
C(3)-stereogenic center (Figure 4).
Figure 3. Ephedrine and pseudoephedrine derived cyclization precursors
15–18. [X=3,4-(OMe)2, 4-OMe, 3-OMe, 2-OMe, H].
Results and Discussion
Cyclization of Uncomplexed
Substrates
Cyclization precursors 24–28
and 34–38 were prepared in
good yield from either (1R,2S)-
ephedrine 19 or (1R,2R)-pseu-
doephedrine 29 by either direct
alkylation or condensation with
the requisite aryl aldehyde fol-
lowed by reduction of the cor-
responding oxazolidine deriva-
tives 20–23 and 30–33. In each
case, the configuration of the
newly generated C(2)-stereo-
genic center within oxazolidines
20–23 and 30–33 was tentatively
assigned based on minimization
of 1,3-steric interactions within
Scheme 3. Reagents and conditions: a) ArCHO, TsOH, C6H6, reflux, 14 h; b) LiAlH4, THF, reflux, 20 h;
c) ArCH2Br, K2CO3, MeCN, reflux, 3 h. [All compounds were isolated in >99:1 d.r.].
the five-membered ring. Of di-
agnostic relevance, the
1H NMR spectra of all of the
(1R,2S)-ephedrine derived sub-
strates 24–28 displayed charac-
teristic coupling constants of
4.1–5.0 Hz between the two ste-
reogenic protons, compared
with 9.7–9.8 Hz for the diaste-
reoisomeric (1R,2R)-pseudoe-
phedrine derivatives 34–38
(Scheme 3).
Exposure of the (1R,2S)-
ephedrine derived substrates
24–28 to a 1:1 mixture of TFA
Scheme 4. Reagents and conditions: a) TFA/H2SO4 (1:1), CH2Cl2, reflux, 30 min. [a] Isolated in>99:1 d.r.
and H2SO4 in CH2Cl2 at reflux [b] Combined yield for 97:3 mixture of 43:48.
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S. G. Davies et al.
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an 88:12 mixture of 39:44 was obtained from identical treat-
ment of (1R,2R)-34. The stereochemical outcome observed
in the cyclization of the (1R,2R)-pseudoephedrine derived
substrates 34–38 is inconsistent with an SN2-type pathway,
but may be rationalized by invoking a stereoselective SN1
process. Thus, a likely general reaction mechanism for the
acid-mediated cyclizations of 34–38 may therefore be pro-
posed: initial protonation of the tertiary amine gives the cor-
responding quaternary ammonium salt (thus preventing azir-
idinium ion formation); protonation of the hydroxyl func-
tionality renders it a good leaving group, and ionization re-
sults in the formation of a benzylic carbocation. The faces of
the planar carbocationic intermediate are rendered diaste-
reotopic by virtue of the adjacent stereogenic center, and
the internal nucleophile may discriminate between them ex-
clusively in favour of forming the trans-diastereoisomer,
since the transition state leading to a trans-tetrahydroisoqui-
noline will be of a considerably lower energy than that lead-
ing to the corresponding cis-tetrahydroisoquinoline, owing
to the developing steric interactions between the C(4)-
phenyl and C(3)-methyl groups in the latter case. As trans-
tetrahydroisoquinolines 39–43 are formed as the major
product from cyclization of all the (1R,2S)-epehdrine de-
rived substrates 24–28 this does not allow prediction as to
the relative importance of either a direct SN2-type or stereo-
selective SN1 mechanistic pathway in these cases.
For the N-monomethoxybenzyl substituted compounds,
higher levels of stereocontrol are observed in the para-me-
thoxy and ortho-methoxy sub-
Figure 4. Chem3D representation of the single crystal X-ray structure of
(3S,4R)-42 (some H atoms have been omitted for clarity).
Analogous cyclization of the (1R,2R)-pseudoephedrine
derived substrates 34–38 also produced trans-tetrahydroiso-
quinolines 39–43 as the major diastereoisomers (Scheme 5),
but in the opposite enantiomeric series, which would be ex-
pected given the known configurations of the C(2)-stereo-
genic centers within (1R,2S)-ephedrine and (1R,2R)-pseu-
doephedrine. The samples of 39–43 isolated from the cycli-
zations of (1R,2R)-pseudoephedrine derived substrates 34–
38 displayed equal and opposite specific rotations to those
isolated upon cyclization of the (1R,2S)-ephedrine derived
substrates 24–28.
stituted cases 25, 27, 35 and 37
relative to the meta-methoxy
substituted analouges 26 and
36. This higher stereocontrol
may be accounted for by invok-
ing a mechanism that proceeds
under the influence of the
ortho- or para-methoxy sub-
stituents via a spirocyclic five-
membered ring intermediate
for which steric compression is
more pronounced than in the
Scheme 5. Reagents and conditions: a) TFA/H2SO4 (1:1), CH2Cl2, reflux, 30 min. [All compounds were isolated
in>99:1 d.r.]; [a] Combined yield for 88:12 mixture of 39:44. [b] Combined yield for 94:6 mixture of 43:48.
corresponding
ring
six-membered
formed
intermediates
under the influence of the
In all cases, substrates 24–28 and 34–38 underwent prefer-
ential cyclization to give the trans-tetrahydroisoquinolines
39–43 in ꢀ87:13 d.r., and the high-yielding conversion of
both the N-benzyl-substituted precursors 28 and 38 implies
that the presence of a methoxy substituent is not a prerequi-
site for cyclization. It is reasonable to assume that the ring
closures are irreversible, since the diastereoisomeric ratios
observed in the cyclizations of the (1R,2S)-ephedrine de-
rived precursors 24–28 are different to those observed upon
cyclization of the corresponding (1R,2R)-pseudoephedrine
derived substrates 34–38. For instance, in the cyclizations of
the 3,4-dimethoxybenzyl substituted precursors, 39 was ob-
tained in >99:1 d.r. from cyclization of (1R,2S)-24, whereas
meta-methoxy group. Assuming that spirocyclic intermedi-
ates feature in the cyclization process there is the possibility
for the formation of regioisomeric products through migra-
tion of either of the two alkyl groups upon subsequent dien-
one-phenol rearrangement. Given these cyclization reactions
give exclusive formation of single regioisomers, a possible
mechanistic rationale is that migration of the group bearing
the phenyl substituent is favoured owing to its greater mi-
gratory aptitude; this interpretation seems reasonable, as
the migrating group must be able to stabilize a developing
positive charge, a role that the N-methylamino group is
unable to perform, since the nitrogen atom is presumably
protonated under the acidic reaction conditions (Figure 5).
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Cyclization of Substituted N-Benzylethanolamines
matic ring had occurred. The remaining (1R,2S)-ephedrine
derived chromium tricarbonyl complexes 53–56 were readily
prepared by a directly analogous procedure involving alkyla-
tion of 51 with the appropriately substituted benzyl bromide.
In each case no migration of the chromium tricarbonyl
moiety was observed.
AHCTUNGTERGNUN[N (1R,2R)-Pseudoephedrine]Cr(CO)3 58 was prepared by
hydrolysis of oxazolidine complex 57 in the presence of
TsOH (ꢁ1.0 equiv) and conc aq HCl at reflux for 15 h,
which gave a mixture of 58 and cyclohexanone (Scheme 7).
Figure 5. Stereoselective cyclization and regioselective rearrangement.
Cyclization of Chromium Tricarbonyl Complexes
The corresponding chromium tricarbonyl complexes of sub-
strates 24–28 and 34–38 were next prepared. [(1R,2S)-Ephe-
drine]Cr(CO)3 51, derived from (1R,2S)-ephedrine 19, was
prepared by reaction of N-Boc protected (1R,2S)-ephedrine
49 with Cr(CO)6 to give 50 in 54% yield (Scheme 6). Subse-
quent N-Boc deprotection was accomplished upon exposure
to neat formic acid giving 51 in quantitative yield. The N-
3,4-dimethoxybenzyl substituted complex 52 was obtained
upon alkylation of 51 with 3,4-dimethoxybenzyl bromide in
1
the presence of K2CO3. The H NMR spectrum of the prod-
uct revealed a three proton aromatic multiplet at dH =6.69–
6.79 ppm and a five proton aromatic multiplet at dH =5.21–
5.55 ppm, clearly indicating that the chromium tricarbonyl
unit was co-ordinated to the phenyl ring and that no migra-
tion to the more electron rich dimethoxy substituted aro-
Scheme 7. Reagents and conditions: a) cyclohexanone, C6H6, reflux, 22 h
then Cr(CO)6, Bu2O, THF, reflux, 48 h; b) TsOH, HCl (conc aq), THF/
H2O (2:1), RT, 15 h; c) ArCH2Br, K2CO3, MeCN, reflux, 3 h; d) ArCHO,
TsOH, CH2Cl2, 4 ꢁ MS then NaBH4, MeOH, RT, 15 h; e) BnBr,
NaHCO3, NaI, EtOH, RT, 63 h. [All compounds were isolated in>99:1
d.r.]. [a] Mixture with cyclohexanaone.
This mixture was immediately treated with 3,4-dimethoxy-
benzyl bromide to give complex (1R,2R)-59 in 61% isolated
yield over the two steps. The 1H NMR spectrum of the
crude reaction mixture again indicated that the chromium
tricarbonyl unit had not undergone migration to the more
electron rich aromatic ring. The corresponding N-methoxy-
benzyl substituted (1R,2R)-pseudoephedrine derived com-
plexes 60–62 were synthesisied by condensation of [(1R,2R)-
pseudoephedrine]Cr(CO)3 58 with the requisite regioisomer
of methoxybenzaldehyde and subsequent reduction of the
resultant oxazolidine complexes with NaBH4, and the N-
benzyl substituted complex 63 was prepared through the
benzylation of complex 58 with BnBr in the presence of a
catalytic quantity of NaI; no migration of the chromium tri-
carbonyl moiety was observed in any case.
In each case, yellow solutions of the cyclization precursor
complexes 52–56 and 59–63 in CH2Cl2 at À208C were treat-
ed with 1.0 equiv of HBF4, but only starting material was re-
turned. Further optimization revealed that excess acid is re-
quired to promote a reaction; the fact that these substrates
Scheme 6. Reagents and conditions: a) Boc2O, Et3N, CH2Cl2, RT, 60 h;
b) Cr(CO)6, Bu2O/THF (10:1), reflux, 48 h; c) HCO2H, RT, 4.5 h;
d) ArCH2Br, K2CO3, MeCN, reflux, 3 h. [All compounds isolated in
>99:1 d.r.].
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require more than one equivalent of acid is consistent with
the hypothesis that the first equivalent of acid protonates
the tertiary amine and excess acid is then required to ach-
ieve further reaction. Upon treatment of 3,4-dimethoxyben-
zyl substituted 59 with acid, the reaction mixture turned
deep purple (indicative of benzylic carbocation formation)
and within 24 h the colour of the solution had reverted to
yellow. After work-up a single product was obtained, which
was tentatively assigned as the corresponding trans-tetrahy-
droisoquinolone complex. This assignment was confirmed
by subsequent oxidative decomplexation, which liberated
trans-39 (Scheme 8); the specific rotation of the product was
(1R,2R)-38 in a ratio of 87:13, respectively. Purification of
the crude reaction mixture by flash column chromatography
enabled the isolation of trans-43 in 28% yield and
>99:1 d.r.
Acid-mediated cyclization of the N-3,4-dimethoxybenzyl-
and N-monomethoxybenzyl substituted (1R,2S)-ephedrine
derived complexes 52, 53, and 55 afforded the desired
N(2),3-dimethyl-4-phenyltetrahydroisoquinolines after de-
complexation: treatment of a solution of 3,4-dimethoxyben-
zyl substituted 52 in CH2Cl2 at À208C with excess HBF4
gave rise to a single product which was tentatively assigned
as the corresponding cis-tetrahydroisoquinoline complex in
>99:1 d.r.[21] Subsequent decomplexation confirmed this as-
signment with the liberation of cis-tetrahydroisoquinoline
3
(3S,4S)-44 (which displayed a diagnostic J coupling constant
of 4.4 Hz between the C(3)H and C(4)H protons) which was
isolated in 75% yield (over the two steps) and >99:1 d.r.,
confirming that the cyclization of 52 had occurred with com-
plete retention of configuration at the benzylic stereogenic
center. Analogous treatment of C(4’)-methoxy substituted
53 with excess HBF4 at À208C gave a single tetrahydroiso-
quinoline complex, with subsequent oxidative decomplexa-
tion giving trans-40 as a single diastereoisomer (>99:1 d.r.)
in 78% yield over the 2 steps. Cyclization of C(2’)-methoxy
substituted 55, followed by decomplexation, gave a 63:37
mixture of (3S,4R)-42 and (S)-64, respectively. Recrystalliza-
tion of the mixture enabled isolation of 42 in 50% yield and
>99:1 d.r. In the case of (1R,2S)-ephedrine derived N-
benzyl substituted complex 56, attemped cyclization was
found to give (S)-65 as the only isolable product after de-
complexation (Scheme 9).
Analogous cyclization of C(3’)-methoxy substituted pre-
cursors (1R,2S)-54 and (1R,2R)-61 also proceeded with ex-
tremely high levels of diastereoselectivity, although in these
cases mixtures of regioisomers were formed (Scheme 10).
Cyclization of (1R,2R)-pseudoephedrine derived complex 61
gave an inseparable 91:9 mixture of complexes 66 and 67,
which, after decomplexation, gave an inseparable 91:9 mix-
ture of trans-41 and another trans-tetrahydroisoquinoline,
which was tentatively assigned as the 5-methoxy substituted
regioisomer 68, in 65% combined yield over the two steps.
Cyclization of the (1R,2S)-ephedrine derived complex 54
produced a separable 86:14 mixture of regioisomeric tetra-
Scheme 8. Reagents and conditions: a) HBF4·OMe2, CH2Cl2, 08C, 2 h;
b) O2, Et2O, hn, 24 h. [All compounds isolated in >99:1 d.r.]. [a] 50:50
ratio of 42:64.
both equal and opposite to that of the product prepared
from cyclization of the uncomplexed epimeric analogue 24
derived from (1R,2S)-ephedrine 19. Acid-mediated cycliza-
tion of C(4’)-methoxy substituted complex 60 gave a single
tetrahydroisoquinoline complex, with oxidative decomplexa-
tion giving trans-40 in 94% yield and >99:1 d.r. Attempted
acid-mediated cyclization of 62 afforded a 50:50 mixture of
trans-42 and (R)-64, contaminated with small amounts of
unidentified impurities after decomplexation. Recrystalliza-
tion of the mixture afforded 42 in 9% yield and >99:1 d.r.
The identity of (R)-64 was confirmed by independent chemi-
cal synthesis: an authentic sample of (RS)-64 was prepared
in 96% yield by alkylation of (RS)-N-methylamphetamine
with 2-methoxybenzylbromide. The formation of (R)-64 in
this system is consistent with reduction occurring as a conse-
quence of a disproportionation
reaction, whereby the secon-
dary alcohol serves as the re-
ducing agent.[20] In this case a
phenyl ketone complex would
be generated which presuma-
bly polymerizes under the
strongly acidic reaction condi-
tions. Cyclization of the N-
benzyl substituted (1R,2S)-
ephedrine derivative 63, fol-
lowed by decomplexation gave
trans-43 along with uncom-
Scheme 9. Reagents and conditions: a) HBF4·OMe2, CH2Cl2, 08C, 2 h; b) O2, Et2O, hn, 24 h. [All compounds
were isolated in >99:1 d.r.]. [a] 63:37 ratio of 42:64.
plexed
starting
material
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Cyclization of Substituted N-Benzylethanolamines
drine derived complexes 52–55
must proceed under the influ-
ence of the methoxy groups.
Ring closure of N-3-methoxy-
benzyl substituted 54 occurs
under the influence of the
meta-methoxy group to give the
six-membered ring intermediate
73 directly (Figure 6), whilst
cyclization of the N-4-methoxy-
benzyl and N-2-methoxybenzyl
substituted complexes 53 and
55 under the influence of the
para-
and
ortho-methoxy
groups, respectively, would ori-
entate the b-methyl group and
arene chromium tricarbonyl
unit cis within the correspond-
ing five-membered ring spirocy-
clic intermediates 78. The great-
er steric compression associated
Scheme 10. Reagents and conditions: a) HBF4·OMe2, CH2Cl2, À208C, 46 h; b) O2, Et2O, hn, 24 h. [All com- with cis-five-membered spirocy-
pounds were isolated in>99:1 d.r.]. [a] Combined yield.
clic intermediates 78 (relative
to cis-73) may manifest itself in
hydroisoquinoline complexes 69 and 70, which were isolated
in 50 and 8% yield, respectively, and in >99:1 d.r. in both
cases. Subsequent oxidative decomplexation confirmed the
cis-configuration within complexes 69 and 70, giving cis-46
(J3,4 =4.6 Hz) in 82% yield upon decomplexation of cis-69,
and cis-71 (J3,4 =3.8 Hz) in quantitative yield after decom-
plexation of cis-70.
a transition state of sufficiently high energy as to prevent
cyclization, and thereby prolongs the lifetime of the benzylic
carbocations 74. A lower energy reaction pathway would
result from intramolecular trapping of the epimerized ben-
zylic carbocations 75 from the unhindered exo face to give
the trans-configured spirocyclic intermediates 76, with subse-
quent rearrangement and loss of a proton accounting for the
observed trans-tetrahydroisoquinoline products 40 and 42
(Figure 7). For the N-3,4-dimethoxybenzyl substituted com-
plex (1R,2S)-52 the cyclization presumably proceeds under
the influence of the meta-methoxy group to give six-mem-
bered ring intermediate 73 directly, leading to the cis-prod-
uct 44, for which steric compression in the transition state is
less severe than the corresponding spirocyclic intermediate
78 formed from cyclization under the influence of the para-
methoxy substituent.
The cyclizations of complexes 52–55 and 59–63 are ren-
dered completely stereoselective (>99:1 d.r.) upon co-ordi-
nation of the substrates to chromium tricarbonyl, owing to
the stereocontrolling influence of the transition metal frag-
ment. Cyclization of the (1R,2R)-pseudoephedrine derived
complexes 59–63 proceeded with retention of configuration
to give the corresponding trans-tetrahydroisoquinolines after
decomplexation. In the case of the N-3,4-dimethoxybenzyl-
and N-3-methoxybenzyl (1R,2S)-ephedrine derived com-
plexes 52 and 54, respectively, the cyclization reactions also
proceeded with retention of configuration to give the corre-
sponding cis-tetrahydroisoquinolines after decomplexation.
The stereochemical outcomes of these reactions, as well as
the increased rates of cyclization versus the uncomplexed
substrates, are consistent with a “double inversion” mecha-
nism involving neighbouring group participation by the
chromium tricarbonyl moiety during the ionization of the
protonated hydroxyl group, which occurs with initial inver-
sion of configuration. Subsequent intramolecular trapping of
the resultant carbocation must occur from the unhindered
exo face, again with inversion, to account for the overall re-
tention of configuration. In contrast, cyclization of the N-4-
methoxybenzyl and N-2-methoxybenzyl substituted (1R,2S)-
ephedrine derived complexes 53 and 55, respectively, pro-
ceeded with complete inversion of configuration. These data
suggest that the cyclization reactions of the (1R,2S)-ephe-
Figure 6. Cyclization with retention of configuration. [Ar=Ph·Cr(CO)3].
Chem. Asian J. 2010, 5, 589 – 604
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S. G. Davies et al.
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standard vacuum line techniques and
glassware that was flame dried and
cooled under nitrogen before use. Sol-
vents were dried according to the pro-
cedure outlined by Grubbs and co-
workers.[22] Water was purified by a
Millipore Elix UV-10 system. All
other solvents were used as supplied
(analytical or HPLC grade) without
prior purification. Organic layers were
dried over MgSO4. Thin layer chroma-
tography was performed on aluminium
plates coated with 60 F254 silica. Plates
were visualized by using UV light
(254 nm), iodine, 1% aq KMnO4, or
10% ethanolic phosphomolybdic acid.
Flash column chromatography was
performed on Kieselgel 60 silica.
Elemental analyses were recorded by
the microanalysis service of the Inor-
ganic Chemistry Laboratory, Universi-
ty of Oxford, UK. Melting points were
recorded by using a Gallenkamp Hot
Stage apparatus and are uncorrected.
Optical rotations were recorded on a
Perkin–Elmer 241 polarimeter with a
water-jacketed 10 cm cell. Specific ro-
tations are reported in 10À1 degcm2 gÀ1
and concentrations in g/100 mL. IR
Figure 7. Cyclization with inversion of configuration. [Ar=Ph·Cr(CO)3].
spectra were recorded by using
a
Bruker Tensor 27 FT-IR spectrometer as either a thin film on NaCl
plates (film) or a KBr disc (KBr), as stated. Selected characteristic peaks
are reported in cmÀ1. NMR spectra were recorded by using Bruker
Avance spectrometers in the deuterated solvent stated. The field was
locked by external referencing to the relevant deuteron resonance. Low-
resolution mass spectra were recorded by using either a VG MassLab
20–250 or a Micromass Platform 1 spectrometer. Accurate mass measure-
ments were run by using either a Bruker MicroTOF, which was internally
calibrated with polyalanine, or a Micromass GCT instrument fitted with
a Scientific Glass Instruments BPX5 column (15 mꢂ0.25 mm) using amyl
acetate as a lock mass.
Conclusions
In conclusion, the acid-mediated cyclization of a range of
differentially substituted N-benzylethanolamines [derived
from (1R,2S)-ephedrine and (1R,2R)-pseudoephedrine] pro-
ceed to give preferential formation of the trans-N(2),3-di-
methyl-4-phenyl-1,2,3,4-tetrahydroisoquinoline
products.
The diastereoselectivities observed during these cyclizations
may be accounted for by the presence of methoxy substitu-
ents around the aromatic ring and their influence upon the
cyclization reaction. The cyclization reactions are rendered
completely diastereostereoselective upon co-ordination of
the precursors to a chromium tricarbonyl unit, proceeding
through a neighboring group participation mechanism with
overall retention of configuration, except where steric
crowding prohibits the formation of a cis-1,2-disubstituted
spirocyclic intermediate; in this case epimerization of the
benzylic carbocation and complete inversion of configura-
tion is observed. The acid-mediated cyclizations of (1R,2S)-
N-(3’,4’-dimethoxybenzyl)ephedrine and the corresponding
chromium tricarbonyl complex are complementary, with the
former giving trans-(3S,4R)-N(2),3-dimethyl-4-phenyl-6,7-di-
methoxy-1,2,3,4-tetrahydroisoquinoline upon exposure to
acid, and the latter affording the corresponding cis-(3S,4S)-
diastereoisomer, after decomplexation.
General Procedure 1: Alkylation
A solution of the amino alcohol (1.0 equiv) and the appropriately substi-
tuted benzylbromide (1.0 equiv) in the specified solvent was heated at
reflux in the presence of K2CO3 (2.0–3.0 equiv) for 3 h. The solution was
then concentrated in vacuo and water was added. The organic layer was
separated and the aqueaous layer was extracted with either CH2Cl2 or
Et2O. The combined organic extracts were then dried, filtered and con-
centrated in vacuo.
General Procedure 2: Reductive Amination
A solution of the amino alcohol (1.0 equiv) and the appropriately substi-
tuted benzaldehyde (1.0 equiv) in C6H6 was treated with a catalytic quan-
tity of TsOH and the resultant mixture was heated at reflux under Dean–
Stark conditions for 10–20 h. The reaction mixture was then concentrated
in vacuo and water was added. The organic layer was separated and the
aqueous layer was extracted with either Et2O or CH2Cl2. The combined
organic extracts were then dried, filtered and concentrated in vacuo to
give the corresponding oxazolidine. A portion of this material (1.0 equiv)
was dissolved in THF and LiAlH4 (ꢁ1.2 equiv) was cautiously added.
The resultant mixture was heated at reflux for 20–30 h then allowed to
cool to RT. The reaction mixture was then cooled to 08C and water and
NaOH (15% aq) were sequentially added. The precipitated aluminium
salts were removed by filtration and filtrate was concentrated in vacuo.
Experimental Section
General Experimental
All reactions involving organometallic or other moisture-sensitive re-
agents were carried out under a nitrogen or argon atmosphere by using
596
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ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Asian J. 2010, 5, 589 – 604

Cyclization of Substituted N-Benzylethanolamines
General Procedure 3: Cyclization of Uncomplexed Substrates
C(4)H), 3.85 (3H, s, OCH3), 4.67 (1H, s, C(2)H), 5.14 (1H, d, J=8.3 Hz,
C(5)H), 6.96–7.61 ppm (9H, m, Ph, Ar); 13C NMR (100 MHz, CDCl3):
d=14.9, 35.6, 55.3, 63.9, 82.3, 98.6, 114.0, 127.7, 128.0, 128.2, 129.8, 130.4,
140.2, 160.6 ppm; MS (CI): m/z: 284 ([M+H]+, 100%). A portion of this
material (2.68 g, 9.44 mmol) was reduced with LiAlH4 (430 mg,
11.3 mmol) to furnish 25 as a colourless oil that solidified on standing
(2.00 g, 74%). Purification of an aliquot by means of recrystallization
(Et2O/hexane) gave an analytically pure sample of 25; m.p.: 50–528C
(Et2O/hexane); [a]2D0 =À33.4 (c 1.0 in CHCl3); IR (KBr disc): n˜max =3400,
3010, 1514, 702; 1H NMR (400 MHz, CDCl3): d=1.00 (3H, d, J=6.8 Hz,
C(2)CH3), 2.19 (3H, s, NCH3), 2.93 (1H, qd, J=6.8, 5.0 Hz, C(2)H), 3.55
(1H, d, J=13.2 Hz, NCHA), 3.59 (1H, d, J=13.2 Hz, NCHB), 3.82 (3H, s,
OCH3), 4.88 (1H, d, J=5.0 Hz, C(1)H), 6.86–7.41 ppm (9H, m, Ph, Ar);
13C NMR (100 MHz, CDCl3): d=9.7, 38.3, 55.2, 58.5, 63.2, 73.7, 113.8,
126.4, 127.1, 128.2, 130.0, 131.7, 143.0, 158.9 ppm; MS (CI): m/z: 286
([M+H]+, 100%); elemental analysis: cacld (%) for C18H23NO2: C 75.8,
H 8.1, N 4.9; found: C 75.9, H 8.4, N 5.0.
A solution of the amino alcohol (1.0 equiv) in CH2Cl2 was treated with
H2SO4 and TFA (1:1, excess) producing a red/purple solution. The mix-
ture was heated at reflux for the specified period of time and then
quenched with aqueous base (either NaOH or K2CO3). The organic layer
was separated and the aqueous layer was extracted with CH2Cl2. The
combined organic extracts were washed with water, then dried, filtered,
and concentrated in vacuo.
General Procedure 4: Cyclization of Chromium Tricarbonyl Complexes
A solution of the amino alcohol complex (1.0 equiv) in CH2Cl2 at À788C
was treated with HBF4·OMe2 (excess) and the resultant solution was
stirred at À788C for 1 h. The reaction mixture was then allowed to warm
to À208C and was quenched by the addition of aqueous base (either
NaOH or K2CO3). The organic layer was separated and the aqueous
layer was extracted with CH2Cl2. The combined organic extracts were
then filtered through a short plug of Al2O3 (eluent CH2Cl2) and the fil-
trate was concentrated in vacuo.
AHCTUNGTERG(NNUN 1R,2S)-1-Phenyl-2-[N-methyl-N-(3’-methoxybenzyl)amino]propan-1-ol
(26): A mixture of (1R,2S)-ephedrine 19 (10.0 g, 60.5 mmol) and 3-me-
thoxybenzaldehyde (8.24 g, 60.5 mmol) in C6H6 (100 mL) was reacted ac-
cording to general procedure 2 to give (2R,4S,5R)-2-(3’-methoxyphenyl)-
General Procedure 5: Decomplexation
N(3),4-dimethyl-5-phenyloxazolidine 22 as
94%). Purification of an aliquot by means of reduced pressure distilla-
a pale yellow oil (16.1 g,
A solution of the relevant complex in Et2O (10 mgmLÀ1) was allowed to
stand in air and sunlight until the yellow solution became colourless
(approx. 24–48 h). The precipitated chromium residues were removed by
filtering the solution through a short plug of celite and the filtrate was
concentrated in vacuo.
tion (160–1728C, 0.06 mm Hg) gave an analytically pure sample of 22;
[a]D20 =À49.1 (c=1.1 in CHCl3); IR (film): n˜max =3010, 700 cmÀ1; H NMR
1
(400 MHz, CDCl3): d=0.80 (3H, d, J=6.4 Hz, C(4)CH3), 2.21 (3H, s,
NCH3), 2.98 (1H, dq, J=8.2, 6.4 Hz, C(4)H), 3.86 (3H, s, OCH3), 4.69
(1H, s, C(2)H), 5.15 (1H, d, J=8.2 Hz, C(5)H), 6.89–7.47 ppm (9H, m,
Ph, Ar); 13C NMR (100 MHz, CDCl3): d=14.8, 35.7, 55.2, 63.9, 82.5, 98.7,
113.6, 115.0, 120.9, 128.0, 128.2, 128.5, 129.5, 129.7, 140.0, 160.0 ppm; MS
(CI): m/z: 284 ([M+H]+, 100%); elemental analysis: calcd (%) for
C18H21NO2: C 76.3; H 7.5; N 4.9; found: C 76.5; H 7.8; N 4.8. A portion
of this material (5.00 g, 17.6 mmol) was reduced with LiAlH4 (800 mg,
21.1 mmol) to furnish 26 as a colourless oil (4.86 g, 96%). Purification of
an aliquot by means of flash column chromatography (eluent Et2O) gave
an analytically pure sample of 26; [a]2D0 =À28.4 (c=1.0 in CHCl3); IR
(film): n˜max =3420, 3010, 703; 1H NMR (400 MHz, CDCl3): d=1.01 (3H,
d, J=6.8 Hz, C(2)CH3), 2.21 (3H, s, NCH3), 2.95 (1H, qd, J=6.8, 5.0 Hz,
C(2)H), 3.32 (1H, br s, OH), 3.59 (1H, d, J=13.5 Hz, NCHA), 3.61 (1H,
d, J=13.5 Hz, NCHB), 3.79 (3H, s, OCH3), 4.88 (1H, d, J=5.0 Hz,
C(1)H), 6.78–7.36 ppm (9H, m, Ph, Ar); 13C NMR (100 MHz, CDCl3):
d=9.7, 38.6, 55.1, 59.0, 63.4, 73.8, 112.6, 114.1, 121.1, 126.4, 127.1, 128.2,
129.4, 141.4, 142.8, 159.9 ppm; MS (CI): m/z: 286 ([M+H]+, 100%); ele-
mental analysis: calcd (%) for C18H23NO2: C 75.8, H 8.1, N 4.9; found:
C 75.9, H 8.4, N 4.9.
ACHTUNGTRENNUNG(1R,2S)-1-Phenyl-2-[N-methyl-N-(3’,4’-dimethoxybenzyl)amino]propan-1-
ol (24):
Method A: (1R,2S)-Ephedrine 19 (1.01 g, 6.11 mmol) was reacted with
freshly distilled 3,4-dimethoxybenzylbromide (1.41 g, 6.10 mmol) in
MeCN (100 mL) according to general procedure 1 for 4 h to give 24, as a
colourless oil (1.71 g, 89%, >99:1 d.r.). Purification of an aliquot by
means of reduced pressure distillation (5 mbar) gave an analytically pure
sample of 24; [a]2D0 =À30.4 (c=0.5 in CHCl3); IR (film): n˜max =3019,
1515, 723 cmÀ1 1H NMR (400 MHz, CDCl3): d=1.02 (3H, d, J=6.8 Hz,
;
C(2)CH3), 2.18 (3H, s, NCH3), 2.96 (1H, qd, J=6.8, 5.3 Hz, C(2)H), 3.55
(2H, app d, J=2.4 Hz, NCH2), 3.83 (3H, s, OCH3), 3.88 (3H, s, OCH3),
4.85 (1H, d, J=5.3 Hz, C(1)H), 6.74–7.35 ppm (8H, m, Ph, Ar);
13C NMR (100 MHz, CDCl3): d=9.7, 38.2, 55.8, 55.9, 58.9, 63.2, 74.1,
110.9, 111.7, 120.7, 126.3, 126.9, 128.0, 132.1, 142.80, 148.0, 149.0 ppm;
MS (CI): m/z: 316 ([M+H]+, 100%); elemental analysis: calcd (%) for
C19H25NO3: C 72.35, H 8.0, N 4.4; found: C 72.0, H 8.4, N 4.4.
Method B: (1R,2S)-Ephedrine 19 (5.00 g, 30.3 mmol) and 3,4-dimethoxy-
benzaldehyde (5.00 g, 30.1 mmol) in C6H6 (80 mL) were reacted accord-
ing to general procedure 2 for 23 h to give 20 (93:7 d.r. crude) as, after
purification by means of recrystallization (CH2Cl2/hexane), a white solid
(7.49 g, 79%,>99:1 d.r.); m.p.: 938C; [a]2D0 =À48.6 (c=1.9 in CHCl3); IR
AHCTUNGTERG(NNUN 1R,2S)-1-Phenyl-2-[N-methyl-N-(2’-methoxybenzyl)amino]propan-1-ol
(27): A mixture of (1R,2S)-ephedrine 19 (8.00 g, 48.4 mmol) and 2-me-
thoxybenzaldehyde (6.59 g, 48.4 mmol) in C6H6 (100 mL) was reacted ac-
cording to general procedure 2 to furnish (2R,4S,5R)-2-(2’-methoxyphen-
1
(KBr disc): n˜max =3010, 1517 cmÀ1; H NMR (400 MHz, CDCl3): dH =0.81
(3H, d, J=6.4 Hz, C(4)CH3), 2.19 (3H, s, NCH3), 2.97 (1H, dq, J=8.1,
6.4 Hz, C(4)H), 3.91 (3H, s, OCH3), 3.95 (3H, s, OCH3), 4.66 (1H, s,
C(2)H), 5.13 (1H, d, J=8.2 Hz, C(5)H), 6.90–7.47 ppm (8H, m, Ph, Ar);
13C NMR (100 MHz, CDCl3): d=14.8, 35.6, 55.8, 55.8, 63.8, 82.3, 98.8,
110.9, 121.2, 127.8, 127.9, 128.0, 128.1, 128.2, 130.9, 140.2, 149.3,
149.9 ppm; MS (CI): m/z: 312 ([M+H]+, 100%); elemental analysis:
calcd (%) for C19H23NO3: C 72.8; H 7.4; N 4.5; found: C 72.9; H 7.6;
N 4.4. A portion of this material (1.95 g, 6.22 mmol) was reduced with
LiAlH4 (354 mg, 9.33 mmol) to furnish 24 as a colourless oil (1.96 g,
quant,>99:1 d.r.).
yl)-N(3),4-dimethyl-5-phenyloxazolidine 23 as
a white solid (12.7 g,
93%,>99:1 d.r.). Purification of an aliquot by means of recrystallization
(Et2O/hexane) gave an analytically pure sample of 23; m.p.: 100–1018C
(Et2O/hexane); [a]D20 =À75.1 (c=1.3 in CHCl3); IR (KBr disc): n˜max
=
3010, 1496, 700 cmÀ1 1H NMR (400 MHz, CDCl3): d=0.83 (3H, d, J=
;
6.4 Hz, C(4)CH3), 2.26 (3H, s, NCH3), 3.04 (1H, dq J 7.7, 6.4, C(4)H),
3.90 (3H, s, OCH3), 5.21 (1H, app d, J=8.1 Hz, C(4)H), 5.31 (1H, s,
C(2)H), 6.95–7.97 ppm (9H, m, Ph, Ar); 13C NMR (100 MHz, CDCl3):
d=14.8, 36.0, 55.6, 63.8, 82.7, 91.8, 110.9, 121.0, 126.1, 127.6, 127.9, 128.2,
128.6, 130.1, 140.3, 159.1 ppm; MS (CI): m/z: 284 ([M+H]+, 100%); ele-
mental analysis: calcd (%) for C18H21NO2: C 76.3, H 7.5, N 4.9; found:
C 76.6, H 7.6, N 4.75. A portion of this material (4.71 g, 16.6 mmol) was
reduced with LiAlH4 (800 mg, 21.1 mmol) to furnish 27 as a white
powder (4.62 g, 97%,>99:1 d.r.). Purification of an aliquot by means of
recrystallization (Et2O/hexane) gave an analytically pure sample of 27;
m.p.: 888C (Et2O/hexane); [a]2D0 =À64.8 (c=0.9 in CHCl3); IR (KBr
ACHTUNGTRENNUNG(1R,2S)-1-Phenyl-2-[N-methyl-N-(4’-methoxybenzyl)amino]propan-1-ol
(25): A mixture of (1R,2S)-ephedrine 19 (5.00 g, 30.3 mmol) and 4-me-
thoxybenzaldehyde (4.12 g, 30.3 mmol) in C6H6 (150 mL) was reacted ac-
cording to general procedure 2 to give (2S,4S,5R)-2-(4’-methoxyphenyl)-
N(3),4-dimethyl-5-phenyloxazolidine 21 as a white solid (8.09 g, 94%,
>99:1 d.r.). Purification of an aliquot by means of recrystallization
(Et2O/hexane) gave an analytically pure sample of 21;[23] m.p.: 85–868C;
[a]D20 =À55.2 (c=1.5 in CHCl3); [a]D20 =À38.9 (c=1.9 in C6H6); IR (KBr
disc): n˜max =3420, 3005, 1495, 704 cmÀ1 1H NMR (400 MHz, CDCl3): d=
;
0.97 (3H, d, J=6.9 Hz, C(2)CH3), 2.15 (3H, s, NCH3), 2.95 (1H, qd, J=
6.9, 4.1 Hz, C(2)H), 3.59 (1H, d, J=13.1 Hz, NCHA), 3.84 (1H, d, J=
13.1 Hz, NCHB), 3.90 (3H, s, OCH3), 4.25 (1H, br s, OH), 4.97 (1H, d,
disc): n˜max =3010, 700 cmÀ1 1H NMR (400 MHz, CDCl3): d=0.80 (3H, d,
;
J=6.5 Hz, C(4)CH3), 2.18 (3H, s, NCH3), 2.96 (1H, dq, J=8.3, 6.5 Hz,
Chem. Asian J. 2010, 5, 589 – 604
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597

S. G. Davies et al.
FULL PAPERS
J=4.1 Hz, C(1)H), 6.91–7.39 ppm (9H, m, Ph, Ar); 13C NMR (100 MHz,
CDCl3): d=9.9, 38.7, 54.8, 55.2, 64.0, 73.7, 110.6, 120.4, 126.4, 126.9,
127.1, 127.6, 128.5, 131.0, 142.5, 158.1 ppm; MS (CI): m/z: 286 ([M+H]+,
100%); elemental analysis: calcd (%) for C18H23NO2: C 75.8, H 8.1,
N 4.9; found: C 76.0, H 8.4, N 4.6.
[a]D20 =À125 (c=0.8 in CHCl3); IR (film): n˜max =3340, 3010, 703 cmÀ1
;
1H NMR (400 MHz, CDCl3): d=0.81 (3H, d, J=6.7 Hz, C(2)CH3), 2.23
(3H, s, NCH3), 2.76 (1H, dq, J=9.8, 6.7 Hz, C(2)H), 3.46 (1H, d, J=
12.8 Hz, NCHA), 3.70 (1H, d, J=12.8 Hz, NCHB), 3.83 (3H, s, OCH3),
4.33 (1H, d, J=9.8 Hz, C(1)H), 6.90–7.35 ppm (9H, m, Ph, Ar);
13C NMR (100 MHz, CDCl3): d=7.1, 35.4, 55.2, 57.6, 64.5, 74.7, 113.9,
127.5, 127.8, 128.3, 130.2, 130.9, 142.2, 159.1 ppm; MS (CI): m/z: 286
([M+H]+, 100%); elemental analysis: calcd (%) for C18H23NO2: C 75.8,
H 8.1, N 4.9; found: C 75.6, H 8.5, N 5.0.
ACHTUNGTRENNUNG(1R,2S)-1-Phenyl-2-(N-methyl-N-benzylamino)propan-1-ol (28): A mix-
ture of (1R,2S)-ephedrine 19 (8.00 g, 48.4 mmol) and BnBr (5.40 mL,
45.4 mmol) in MeCN (50 mL) was reacted according to general procedure
1 to furnish, after recrystallization (Et2O/hexane) 28 as a white solid
(7.66 g, 62%,>99:1 d.r.); m.p.: 45–468C (Et2O/hexane) (49–518C)[24]
[a]2D0 =À29.7 (c=1.5 in CHCl3) {[a]D20 =À29.5 (c=2.35 in CHCl3)}[24]
;
;
AHCTUNGTERG(NNUN 1R,2R)-1-Phenyl-2-[N-methyl-N-(3’-methoxybenzyl)amino]propan-1-ol
(36): A mixture of (1R,2R)-pseudoephedrine 29 (10.0 g, 60.5 mmol) and
3-methoxybenzaldehyde (8.24 g, 60.5 mmol) in C6H6 (100 mL) was react-
ed according to general procedure 2 to give (2R,4R,5R)-2-(3’-methoxy-
1H NMR (400 MHz, CDCl3): d=1.00 (3H, d, J=6.8 Hz, C(2)CH3), 2.20
(3H, s, NCH3), 2.94 (1H, qd, J=6.8, 4.9 Hz, C(2)H), 3.46 (1H, br s, OH),
3.61 (1H, d, J=13.5 Hz, NCHA), 3.64 (1H, d, J=13.5 Hz, NCHB), 4.89
(1H, d, J=4.9 Hz, C(1)H), 7.24–7.35 ppm (10H, m, Ph); 13C NMR
(100 MHz, CDCl3): d=9.7, 38.6, 59.1, 63.5, 73.7, 126.4, 127.1, 127.5, 127.8,
128.5, 129.2, 139.7, 142.9 ppm; MS (CI): m/z: 256 ([M+H]+, 100%).
phenyl)-N(3),4-dimethyl-5-phenyloxazolidine 32 as
a colourless oil
(16.3 g, 95%). Purification of an aliquot by means of reduced pressure
distillation (b.p.: 152–1608C, 0.06 mm Hg) gave an analytically pure
sample of 32 that solidified up on standing; m.p.: 588C; [a]2D0 =À44.0 (c=
1.0 in CHCl3); IR (KBr disc): n˜max =3010, 700 cmÀ1 1H NMR (400 MHz,
;
ACHTUNGTRENNUNG(1R,2R)-1-Phenyl-2-[N-methyl-N-(3’,4’-dimethoxybenzyl)amino]propan-
CDCl3): d=1.25 (3H, d, J=6.0 Hz, C(4)CH3), 2.25 (3H, s, NCH3), 2.58
(1H, dq, J=8.8, 6.0 Hz, C(4)H), 3.86 (3H, s, OCH3), 4.78 (1H, d, J=
8.8 Hz, C(5)H), 4.95 (1H, s, C(2)H), 6.90–7.46 ppm (9H, m, Ph, Ar);
13C NMR (100 MHz, CDCl3): d=14.2, 35.2, 55.2, 68.8, 86.6, 99.5, 113.1,
115.1, 120.6, 126.9, 127.9, 128.6, 129.5, 140.6, 141.3, 160.0 ppm; MS (CI):
m/z: 284 ([M+H]+, 100%); elemental analysis: calcd (%) for
C18H21NO2: C 76.3, H 7.5, N 4.9; found: C 76.1, H 7.6, N 4.8. A portion of
this material (5.03 g, 17.7 mmol) was reduced with LiAlH4 (800 mg,
21.1 mmol) to furnish 36 as a colourless oil (4.77 g, 94%). Purification of
an aliquot by means of flash column chromatography (eluent Et2O) gave
an analytically pure sample of 36; [a]2D0 =À121 (c=1.0 in CHCl3); IR
1-ol (34):
Method A: (1R,2R)-Pseudoephedrine 29 (1.37 g, 8.29 mmol) was reacted
with freshly distilled 3,4-dimethoxybenzylbromide (1.92 g, 8.31 mmol) in
MeCN (100 mL) according to general procedure 1 for 5 h to give 34 as a
white solid (2.60 g, 99%,>99:1 d.r.). Purification of an aliquot by means
of recrystallization (Et2O/hexane) gave an analytically pure sample of 34;
m.p.: 77–788C (Et2O/hexane);[a]2D0 =À131 (c=1.0 in CHCl3); IR (KBr
disc): n˜max =3340, 3010, 704 cmÀ1 1H NMR (400 MHz, CDCl3): d=0.81
;
(3H, d, J=6.6 Hz, C(2)CH3), 2.25 (3H, s, NCH3), 2.76 (1H, dq, J=9.7,
6.6 Hz, C(2)H), 3.45 (1H, d, J=12.9 Hz, NCHA), 3.72 (1H, d, J=
12.9 Hz, NCHB), 3.90 (3H, s, OCH3), 3.92 (3H, s, OCH3), 4.33 (1H, d,
J=9.7 Hz, C(1)H), 6.82–7.34 ppm (8H, m, Ph, Ar); 13C NMR (100 MHz,
CDCl3): d=7.1, 35.6, 55.8, 57.8, 64.4, 74.7, 111.0, 111.8, 121.0, 127.3,
127.4, 127.6, 128.1, 131.2, 141.9, 148.3, 149.1 ppm; MS (CI): m/z: 316
([M+H]+, 100%); elemental analysis: calcd (%) for C19H25NO3; C 72.35,
H 8.0, N 4.4; found: C 72.6, H 8.2, N 4.3.
1
(film): n˜max =3350, 3010, 1496, 702 cmÀ1; H NMR (400 MHz, CDCl3): d=
0.81 (3H, d, J=6.7 Hz, C(2)CH3), 2.25 (3H, s, NCH3), 2.76 (1H, dq, J=
9.7, 6.7 Hz, C(2)H), 3.49 (1H, d, J=13.0 Hz, NCHA), 3.73 (1H, d, J=
13.0 Hz, NCHB), 3.83 (3H, s, OCH3), 4.32 (1H, d, J=9.7 Hz, C(1)H),
5.17 (1H, br s, OH), 6.82–7.35 ppm (9H, m, Ph, Ar); 13C NMR
(100 MHz, CDCl3): d=7.1, 35.7, 55.2, 58.2, 64.9, 74.8, 112.9, 114.4, 121.4,
127.5, 127.9, 128.4, 129.6, 140.5, 142.1, 160.0 ppm; MS (CI): m/z: 286
([M+H]+, 100%); elemental analysis: calcd (%) for C18H23NO2: C 75.8,
H 8.1, N 4.9; found: C 75.6, H, 8.2, N 4.45.
Method B: (1R,2R)-Pseudoephedrine 29 (9.12 g, 55.2 mmol) and 3,4-di-
methoxybenzaldehyde (9.17 g, 55.2 mmol) in C6H6 (100 mL) were reacted
according to general procedure 2 for 14 h to give, after purification by
means of recrystallization (pentane/Et2O), (2R,4R,5R)-2-(3’,4’-dimethoxy-
phenyl)-N(3),4-dimethyl-5-phenyloxazolidine 30 as a white solid (17.3 g,
quant,>99:1 d.r.); m.p.: 54–568C; [a]2D0 =À47.1 (c=1.0 in CHCl3); IR
AHCTUNGTERG(NNUN 1R,2R)-1-Phenyl-2-[N-methyl-N-(2’-methoxybenzyl)amino]propan-1-ol
(37): A mixture of (1R,2R)-pseudoephedrine 29 (8.00 g, 48.4 mmol) and
2-methoxybenzaldehyde (6.59 g, 48.4 mmol) in C6H6 (100 mL) was react-
ed according to general procedure 2 to give, after purification by means
of reduced pressure distillation (1808C, 0.06 mmHg), (2R,4R,5R)-2-(2’-
methoxyphenyl)-N(3),4-dimethyl-5-phenyloxazolidine 33 as a colourless
oil (12.5 g, 91%,>99:1 d.r.); [a]2D0 =À4.84 (c=1.0 in CHCl3); IR (film):
(KBr disc): n˜max =3008, 700 cmÀ1 1H NMR (400 MHz, CDCl3): d=1.25
;
(3H, d, J=6.0 Hz, C(4)CH3), 2.22 (3H, s, NCH3), 2.54 (1H, dq, J=8.7,
6.0 Hz, C(4)H), 3.90 (3H, s, OCH3), 3.95 (3H, s, OCH3), 4.76 (1H, d, J=
8.7 Hz, C(5)H), 4.91 (1H, s, C(2)H), 6.86–7.45 ppm (8H, m, Ph, Ar);
13C NMR (100 MHz, CDCl3): d=14.2, 35.1, 55.8, 68.8, 86.3, 99.6, 110.4,
110.6, 120.9, 126.8, 127.1, 128.5, 128.6, 132.0, 140.7, 149.4, 149.9 ppm; MS
(CI): m/z: 314 ([M+H]+, 100%); elemental analysis: calcd (%) for
C19H23NO3: C 72.8; H 7.4; N 4.5; found: C 72.9; H 7.6; N 4.4. A portion
of this material (3.59 g, 11.5 mmol) in MeOH (40 mL) was reduced with
NaBH4 (1.00 g, 26.4 mmol) according to general procedure 2 to give 34 as
a colourless oil (3.60 g, 99%,>99:1 d.r.).
n˜max =3010, 1495, 700 cmÀ1 1H NMR (400 MHz, CDCl3): d=1.24 (3H, d,
;
J=6.1 Hz, C(4)CH3), 2.26 (3H, s, NCH3), 2.58 (1H, dq, J=8.7, 6.1 Hz,
C(4)H), 3.87 (3H, s, OCH3), 4.75 (1H, d, J=8.7 Hz, C(5)H), 5.58 (1H, s,
C(2)H), 6.90–7.76 ppm (9H, m, Ph, Ar); 13C NMR (100 MHz, CDCl3):
d=14.2, 35.3, 55.6, 69.0, 86.3, 92.4, 110.8, 121.1, 126.9, 127.0, 127.8, 128.3,
128.5, 129.9, 140.9, 158.6 ppm; MS (CI): m/z: 284 ([M+H]+, 100%); ele-
mental analysis: calcd (%) for C18H21NO2: C 76.3, H 7.5, N 4.9; found:
C 76.6, H 7.5, N 4.8. A portion of this material (5.03 g, 17.7 mmol) was re-
duced with LiAlH4 (800 mg, 21.1 mmol) to give 37 as a white solid
(4.62 g, 91%). Purification of an aliquot by means of recrystallization
(Et2O/hexane) gave an analytically pure sample of 37; m.p.: 62–658C
(Et2O/hexane); [a]2D0 =À120 (c=1.3 in CHCl3); IR (film): n˜max =3360,
ACHTUNGTRENNUNG(1R,2R)-1-Phenyl-2-[N-methyl-N-(4’-methoxybenzyl)amino]propan-1-ol
(35): A mixture of (1R,2R)-pseudoephedrine 29 (5.00 g, 30.3 mmol) and
4-methoxybenzaldehyde (4.12 g, 30.3 mmol) in C6H6 (150 mL) was react-
ed according to general procedure 2 to give (2R,4R,5R)-2-(4’-methoxy-
phenyl)-N(3),4-dimethyl-5-phenyloxazolidine 31 as an oil that solidified
on standing (7.32 g, 85%). Purification of an aliquot by means of recrys-
tallization (Et2O/hexane) gave an analytically pure sample of 31; m.p.:
658C (Et2O/hexane); [a]2D0 =À51.0 (c=2.2 in CHCl3); IR (KBr disc):
3010, 1496, 702 cmÀ1 1H NMR (400 MHz, CDCl3): d=0.82 (3H, d, J=
;
6.7 Hz, C(2)CH3), 2.23 (3H, s, NCH3), 2.77 (1H, dq, J=9.7, 6.7 Hz,
C(2)H), 3.47 (1H, d, J=12.7 Hz, NCHA), 3.81 (1H, d, J=12.7 Hz,
NCHB), 3.88 (3H, s, OCH3), 4.34 (1H, d, J=9.7 Hz, C(1)H), 5.37 (1H, br
s, OH), 6.90–7.37 ppm (9H, m, Ph, Ar); 13C NMR (100 MHz, CDCl3):
d=7.3, 36.3, 52.8, 55.1, 65.5, 75.0, 110.5, 120.3, 127.0, 127.6, 127.7, 128.3,
128.8, 131.0, 142.5, 158.3 ppm; MS (CI): m/z: 286 ([M+H]+, 100%); ele-
mental analysis: calcd (%) for C18H23NO2: C 75.8, H 8.1, N 4.9; found:
C 76.0, H 8.4, N 4.95.
n˜max =3010, 700 cmÀ1 1H NMR (400 MHz, CDCl3): d=1.26 (3H, d, J=
;
6.1 Hz, C(4)CH3), 2.22 (3H, s, NCH3), 2.55 (1H, dq, J=8.7, 6.1 Hz,
C(4)H), 3.83 (3H, s, OCH3), 4.78 (1H, d, J=8.7 Hz, C(5)H), 4.94 (1H, s,
C(2)H), 6.95–7.53 ppm (9H, m, Ph, Ar); 13C NMR (100 MHz, CDCl3):
d=14.3, 35.0, 55.3, 68.8, 86.4, 99.4, 113.9, 126.8, 128.0, 128.5, 129.4, 131.8,
140.8, 160.5 ppm; MS (CI): m/z: 284 ([M+H]+, 100%); elemental analy-
sis: calcd (%) for C18H21NO2: C 76.3, H 7.5, N 4.9; found: C 76.2, H 7.8,
N 4.9. A portion of this material (2.50 g, 8.80 mmol) was reduced with
LiAlH4 (400 mg, 10.5 mmol) to give 35 as a colourless oil (4.77 g, 94%);
AHCTUNGTRENNUNG
598
www.chemasianj.org
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Asian J. 2010, 5, 589 – 604

Cyclization of Substituted N-Benzylethanolamines
(4.30 mL, 36.2 mmol) in MeCN (50 mL) was reacted according to general
procedure 1 to give, after recrystallization (CH2Cl2/hexane), 38 as a white
solid (7.18 g, 77%,>99:1 d.r.); m.p.: 57–588C; [a]2D0 =À125 (c=1.5 in
CHCl3); 1H NMR (400 MHz, CDCl3): d=0.82 (3H, d, J=6.6 Hz,
C(2)CH3), 2.24 (3H, s, NCH3), 2.76 (1H, dq, J=9.7, 6.6 Hz, C(2)H), 3.52
(1H, d, J=12.9 Hz, NCHA), 3.76 (1H, d, J=12.9 Hz, NCHB), 4.33 (1H,
d, J=9.7 Hz, C(1)H), 5.24 (1H, br s, OH), 7.26–7.38 ppm (10H, m, Ph);
13C NMR (100 MHz, CDCl3): d=7.2, 35.7, 58.2, 64.9, 74.8, 127.6, 127.9,
128.1, 128.4, 128.7, 129.2, 138.9, 142.3 ppm; MS (CI): m/z: 256 ([M+H]+,
100%).
(25 mL) was cyclized according to general procedure 3 at 408C for 2.5 h
to give 42 (>99:1 d.r. crude) as a pale yellow solid (269 mg, 57%,
>99:1 d.r.). Purification of an aliquot by means of recrystallization
(Et2O/hexane) gave an analytically pure sample of 42; m.p.: 114–1168C
(Et2O/hexane); [a]D20 =À64.5 (c=0.5 in CHCl3); IR (KBr disc): n˜max
=
3005, 700 cmÀ1 1H NMR (400 MHz, CDCl3): d=1.07 (3H, d, J=6.4 Hz,
;
C(3)CH3), 2.47 (3H, s, NCH3), 2.73 (1H, dq, J=8.0, 6.4 Hz, C(3)H), 3.81
(1H, d, J=8.0 Hz, C(4)H), 3.85 (3H, s, OCH3), 3.63 (1H, d, J=16.3 Hz,
C(1)HA), 3.98 (1H, d, J=16.3 Hz, C(1)HB), 6.36–7.31 ppm (8H, m, Ph,
Ar); 13C NMR (100 MHz, CDCl3): d=15.8, 41.3, 52.3, 52.1, 55.2, 61.7,
106.9, 122.2, 123.7, 126.4, 126.6, 128.3, 129.7, 139.2, 145.4, 155.7 ppm; MS
(CI): m/z: 268 ([M+H]+, 100%); elemental analysis: calcd (%) for
C18H21NO: C 80.9, H 7.9, N 5.2; found: C 81.2, H 7.75, N 5.0.
ACHTUNGTRENNUNG(3S,4R)-N(2),3-Dimethyl-4-phenyl-6,7-dimethoxy-1,2,3,4-tetrahydroiso-
quinoline [(3S,4R)-39]: A solution of 24 (685 mg, 2.17 mmol) in CH2Cl2
(12 mL) was reacted according to general procedure 3 at 408C for 30 min
to give 39 (>99:1 d.r. crude) as a brown oil (480 mg, 74%, >99:1 d.r.).
Purification of an aliquot by means of reduced pressure distillation
(5 mbar) gave an analytically pure sample of 39; [a]2D0 =À13.7 (c=1.3 in
AHCTUNGTERG(NNUN 3S,4R)- and (3S,4S)-N(2),3-Dimethyl-4-phenyl-1,2,3,4-tetrahydroisoqui-
noline [(3S,4R)-43] and [(3S,4S)-48]: A solution of 28 (2.00 g, 7.83 mmol)
in CH2Cl2 (50 mL) was reacted according to general procedure 3 at 408C
for 5 h to give a 97:3 mixture of 43 and 48 respectively. Purification of
the residue by means of flash column chromatography (eluent Et2O)
gave a 97:3 mixture of 43 and 48 as a white solid (1.80 g, 97%). Data for
43: 1H NMR (400 MHz, CDCl3): d=1.09 (3H, d, J=6.3 Hz, C(3)CH3),
2.45 (3H, s, NCH3), 2.75 (1H, dq, J=8.3, 6.3 Hz, C(3)H), 3.85 (1H, d,
J=8.3 Hz, C(4)H), 3.86 (2H, m, C(1)H2), 6.73–7.33 ppm (9H, m, Ph,
Ar). Data for mixture: MS (CI): m/z: 237 ([M]+, 100%); elemental anal-
ysis: calcd (%) for C17H19N: C 86.0, H 8.1, N 5.9; found: C 85.7, H 8.2,
N 6.3. Subsequent recrystallization (Et2O/hexane) of an aliquot enabled
the isolation of a diastereoisomerically pure sample of 48; m.p.: 102–
CHCl3); IR (film): n˜max =3010, 1514, 705 cmÀ1 1H NMR (400 MHz,
;
CDCl3): d=1.09 (3H, d, J=6.4 Hz, C(3)CH3), 2.44 (3H, s, NCH3), 2.73
(1H, dq, J=8.0, 6.4 Hz, C(3)H), 3.60 (3H, s, OCH3), 3.75 (1H, d, J=
8.0 Hz, C(4)H), 3.81 (2H, br s, C(1)H2), 3.86 (3H, s, OCH3), 6.19 (1H, s,
Ar), 6.56 (1H, s, Ar), 7.12–7.32 ppm (5H, m, Ph); 13C NMR (100 MHz,
CDCl3): d=16.0, 40.7, 51.7, 55.8 (2C), 57.0, 62.4, 108.5, 112.6, 126.2,
128.1, 128.6, 129.4, 129.6, 145.1, 147.4, 147.6 ppm; MS (CI): m/z: 297
+
([M]+, 100%); HRMS (CI+) C19H23NO3 ([M]+) requires 297.1723;
found 297.1728.
ACHTUNGTRENNUNG(3S,4R)-N(2),3-Dimethyl-4-phenyl-6-methoxy-1,2,3,4-tetrahydroisoquino-
1038C (Et2O/hexane); [a]D20 =+160 (c=0.2 in CHCl3); IR (film): n˜max
3005, 700 cmÀ1 1H NMR (400 MHz, CDCl3): d=0.86 (3H, d, J=6.6 Hz,
=
line [(3S,4R)-40]: A solution of 25 (1.18 g, 4.12 mmol) in CH2Cl2 (50 mL)
was reacted according to general procedure 3 at 408C for 1 h to give 40
(97:3 d.r. crude) as a white solid (1.05 g, 92%,>99:1 d.r.). Purification of
the residue by means of recrystallization (Et2O/hexane) gave 40 as a
white crystalline solid; m.p.: 75–768C (Et2O/hexane); [a]2D0 =À3.82 (c=
;
C(3)CH3), 2.40 (3H, s, NCH3), 2.88 (1H, dq, J=6.6, 4.5 Hz, C(3)H), 3.56
(1H, d, J=15.5 Hz, C(1)HA), 3.99 (1H, d, J=15.5 Hz, C(1)HB), 4.10
(1H, d, J=4.5 Hz, C(4)H), 6.95–7.28 ppm (9H, m, Ph, Ar); 13C NMR
(100 MHz, CDCl3): d=16.3, 41.1, 52.3, 57.8, 62.6, 125.9, 126.0, 126.5,
127.1, 128.4, 129.8, 130.0, 134.6, 138.1, 145.3; MS (CI): m/z: 237 ([M]+,
100%); HRMS (CI+) C17H19N+ ([M]+) requires 237.1517; found
237.1519; elemental analysis: calcd (%) for C17H19N: C 86.0, H 8.1, N 5.9;
found: C 86.35, H 8.1, N 5.9.
0.8 in CHCl3); IR (KBr disc): n˜max =1505, 703 cmÀ1 1H NMR (400 MHz,
;
CDCl3): d=1.08 (3H, d, J=6.4 Hz, C(3)CH3), 2.43 (3H, s, NCH3), 2.73
(1H, dq, J=8.4, 6.4 Hz, C(3)H), 3.62 (3H, s, OCH3), 3.77 (1H, d, J=
8.4 Hz, C(4)H), 3.80 (2H, br s, C(1)H2), 6.27 (1H, d, J=2.7 Hz, C(5)H),
6.70 (1H, dd, J=8.4, 2.7 Hz, C(7)H), 7.00 (1H, d, J=8.4 Hz, C(8)H),
7.13–7.32 ppm (5H, m, Ph); 13C NMR (100 MHz, C6D6): d=14.4, 41.1,
52.7, 54.1, 55.6, 61.9, 112.7, 114.6, 126.3, 127.0, 127.3, 127.8, 129.6, 138.8,
145.8, 158.7 ppm; MS (CI): m/z: 268 ([M+H]+, 100%); elemental analy-
sis: calcd (%) for C18H21NO: C 80.9, H 7.9, N 5.2; found: C 81.0, H 8.05,
N 5.2.
AHCTUNGTERG(NNUN 3R,4S)-N(2),3-Dimethyl-4-phenyl-6,7-dimethoxy-1,2,3,4-tetrahydroiso-
quinoline [(3R,4S)-39]: A solution of 34 (641 mg, 2.03 mmol) in CH2Cl2
(11.0 mL) was cyclized according to general procedure 3 for 30 min at
408C to give an 88:12 mixture of 39 and 44 respectively. Purification of
the residue by using flash column chromatography (eluent Et2O) gave an
inseparable 88:12 mixture of 39 and 44 as a colourless oil (480 mg, 79%);
MS (CI): m/z: 298 ([M+H]+, 100%).
ACHTUNGTRENNUNG(3S,4R)- and (3S,4S)-N(2),3-Dimethyl-4-phenyl-7-methoxy-1,2,3,4-tetra-
hydroisoquinoline [(3S,4R)-41] and [(3S,4S)-46]: A solution of 26 (2.24 g,
7.85 mmol) in CH2Cl2 (25 mL) was reacted according to general proce-
dure 3 at 408C for 1.5 h to give 41 (93:7 d.r. crude) as a pale brown oil.
Purification of the residue by means of flash column chromatography
(eluent Et2O) gave 41 which was recrystallized (Et2O/hexane) to give 41
as a white solid (1.18 g, 56%); m.p.: 121.58C; [a]2D0 =+133 (c=0.05 in
AHCTUNGTRENNUNG
A
(50 mL) was cyclized according to general procedure 3 at 408C for 1 h to
give 40 (93:7 d.r. crude) as a pale-yellow oil (750 mg, 92%). Purification
of the residue by means of flash column chromatography (eluent Et2O)
and subsequent recrystallization (Et2O/hexane) gave 40 as a white crys-
talline solid (>99:1 d.r.); m.p.: 758C; [a]2D0 =+4.25 (c=0.5 in CHCl3); MS
(CI): m/z: 267 ([M]+, 100%); elemental analysis: calcd (%) for
C18H21NO: C 80.9, H 7.9, N 5.2; found: C 80.8, H 8.2, N 5.0.
CHCl3); IR (KBr disc): n˜max =3010, 1504, 702 cmÀ1 1H NMR (400 MHz,
;
CDCl3): d=1.08 (3H, d, J=6.4 Hz, C(3)CH3), 2.44 (3H, s, NCH3), 2.74
(1H, dq, J=8.5, 6.4 Hz, C(3)H), 3.76 (1H, d, J=8.5 Hz, C(4)H), 3.77
(3H, s, OCH3), 3.84 (2H, br s, C(1)H2), 6.61–7.32 ppm (8H, m, Ph, Ar);
13C NMR (100 MHz, CDCl3): d=16.3, 40.8, 51.5, 55.1, 57.9, 62.6, 110.4,
112.9, 126.5, 127.1, 128.5, 129.7, 131.1, 135.7, 145.6, 157.8 ppm; MS (CI):
m/z: 267 ([M]+, 100%); elemental analysis: calcd (%) for C18H21NO:
C 80.9, H 7.9, N 5.2; found: C 80.7, H 8.3, N 5.1. Further elution gave 46
as a colourless oil that solidified on standing (42 mg, 2%); m.p.: 41–
428C; [a]2D0 =À45.4 (c=0.7 in CHCl3); IR (KBr disc): n˜max =3018, 1504,
704; 1H NMR (400 MHz, CDCl3): d=0.84 (3H, d, J=6.6 Hz, C(3)CH3),
2.39 (3H, s, NCH3), 2.86 (1H, qd, J=6.6, 4.6 Hz, C(3)H), 3.78 (3H, s,
OCH3), 3.53 (1H, d, J=15.5 Hz, C(1)HA), 3.95 (1H, d, J=15.5 Hz,
C(1)HB), 4.05 (1H, d, J=4.6 Hz, C(4)H), 6.62–7.29 ppm (8H, m, Ph,
Ar); 13C NMR (100 MHz, CDCl3): d=14.3, 42.2, 50.4, 55.1, 57.1, 59.2,
110.4, 112.8, 126.2, 130.1, 130.6, 130.9, 131.1, 136.0, 143.3, 157.8 ppm; MS
(CI): m/z: 267 ([M]+, 100%); elemental analysis: calcd (%) for
C18H21NO: C 80.9, H 7.9, N 5.2; found: C 81.1, H 8.3, N 5.15.
AHCTUNGTERG(NNUN 3R,4S)- and (3R,4R)-N(2),3-Dimethyl-4-phenyl-7-methoxy-1,2,3,4-tetra-
hydroisoquinoline [(3R,4S)-41] and [(3R,4R)-46]: A solution of 36 (1.69 g,
5.92 mmol) in CH2Cl2 (50 mL) was cyclized according to general proce-
dure 3 at 408C for 1.75 h to give a 87:13 mixture of 41 and 46, respective-
ly, as a red oil. Purification of the residue by means of flash column chro-
matography (eluent Et2O) enabled isolation of the minor component
which was recrystallized (Et2O/hexane) to give 46 as a white solid
(32 mg, 4%, >99:1 d.r.); m.p.: 121–1228C; [a]2D0 =À145 (c=0.05 CHCl3);
MS (CI): m/z: 267 ([M]+, 100%); elemental analysis: calcd (%) for
C18H21NO: C 80.9, H 7.9, N 5.2; found: C 80.6, H 8.3, N 5.0. Further elu-
tion gave 41 as a colourless oil that solidified on standing (649 mg,
41%,>99:1 d.r.); m.p.: 41–428C; [a]2D0 =+44.9 (c=0.9 in CHCl3); MS
(CI): m/z: 267 ([M]+, 100%); elemental analysis: calcd (%) for
C18H21NO: C 80.9, H 7.9, N 5.2; found: C 81.2, H 8.3, N 5.1.
A
ACHTUNGTRENNUNG
A
Chem. Asian J. 2010, 5, 589 – 604
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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599

S. G. Davies et al.
FULL PAPERS
was reacted according to general procedure 3 at 408C for 5 h to give 42
(99:1 d.r. crude) as a pale yellow solid. Purification of the residue by
means of recrystallization (Et2O/hexane) furnished 42 as a white crystal-
line solid (1.57 g, 91%,>99:1 d.r.); m.p.: 114–1168C (Et2O/hexane);
[a]2D0 =+65.5 (c=1.1 in CHCl3); MS (CI): m/z: 268 ([M+H]+, 100%); el-
emental analysis: calcd (%) for C18H21NO: C 80.9, H 7.9, N 5.2; found:
C 80.6, H 8.2, N 5.5.
15 mL) at RT was left to stand for 4.5 h concentrated in vacuo. The resi-
due was treated with 2.0m aq NaOH and the aqueous layer was extracted
with Et2O (10 mL). The combined organic extracts were concentrated in
vacuo to give 51 as a yellow solid (330 mg, quant,>99:1 d.r.). Purification
of an aliquot by means of recrystallization (Et2O/hexane) gave an analyt-
ically pure sample of 51; m.p.: 92–978C (dec); [a]2D0 =À33.0 (c=0.2 in
CHCl3); IR (KBr disc): n˜max =1970, 1885 cmÀ1 1H NMR (400 MHz,
;
CDCl3): d=0.93 (3H, d, J=6.5 Hz, C(2)CH3), 2.48 (3H, s, NCH3), 2.72
(1H, qd, J=6.5, 3.4 Hz, C(2)H), 4.46 (1H, d, J=3.4 Hz, C(1)H), 5.16–
5.66 ppm (5H, m, ArCr(CO)3); MS (CI): m/z: 302 ([M+H]+, 100%); ele-
mental analysis: calcd (%) for C13H15CrNO4: C 51.8, H 5.0, N 4.65;
found: C 51.9, H 5.0, N 4.7.
X-ray Crystal Structure Determination of [(3R,4S)-42]
Data were collected by using an Enraf–Nonius CAD4-F 4-circle diffrac-
tometer with graphite monochromated CuKa radiation using standard
procedures at 190 K. The structure was solved by direct methods
(SIR92); all non-hydrogen atoms were refined with anisotropic thermal
parameters. Hydrogen atoms were added at idealized positions. The
structure was refined using CRYSTALS.[25]
AHCTUNGTERG{NNUN (1R,2S)-1-Phenyl-2-[N-methyl-N-(3’,4’-dimethoxybenzyl)amino]propan-
1-ol}tricarbonylchromium(0) (52): A mixture of 51 (991 mg, 3.29 mmol)
and freshly distilled 3,4-dimethoxybenzylbromide (760 mg, 3.29 mmol) in
MeCN (40 mL) was reacted according to general procedure 1 for 3 h to
give 52 as a yellow oil. Purification of the residue by means of flash colo-
umn chromatography (eluent Et2O) furnished 52 as a yellow oil (727 mg,
49%,>99:1 d.r.); 1H NMR (400 MHz, CDCl3): d=1.11 (3H, d, J=
6.7 Hz, C(2)CH3) 2.23 (3H, s, NCH3), 2.78 (1H, qd, J=6.7, 6.2 Hz,
C(2)H), 3.45 (1H, d, J=13.2 Hz, NCHA), 3.51 (1H, d, J=13.2 Hz,
NCHB), 3.85 (3H, s, OCH3), 3.87 (3H, s, OCH3), 4.38 (1H, d, J=6.2 Hz,
C(1)H), 5.21–5.55 (5H, m, ArCr(CO)3), 6.69–6.79 ppm (3H, m, Ar); MS
(CI): m/z: 452 ([M+H]+, 100%).
X-ray crystal structure data for [(3R,4S)-42] [C18H21NO]: M=267.37, or-
thorhombic, space group P212121; a=5.978(2), b=9.257(1), c=
26.799(4) ꢁ; V=1482.9(6) ꢁ3, Z=4, m=0.062 mmÀ1, colourless block,
crystal dimensions=0.4ꢂ0.6ꢂ0.8 mm3. A total of 1804 unique reflections
were measured for 5<q<27 and 1645 reflections were used in the refine-
ment. The final parameters were wR2 =0.091 and R1 =0.075 [I>3.0s(I)].
CCDC 746820 [(3R,4S)-42] contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge from The
Cambridge Crystallographic Data Centre at www.ccdc.cam.ac.uk/data_
request/cif
AHCTUNGTERG{NNUN (1R,2S)-1-Phenyl-2-[N-methyl-N-(4’-methoxybenzyl)amino]propan-1-ol}-
tricarbonylchromium(0) (53): A mixture of 51 (330 mg, 1.09 mmol) and
freshly distilled 4-methoxybenzylbromide (220 mg, 1.09 mmol) in CH2Cl2
(30 mL) was reacted according to general procedure 1 at RT for 28 h to
give 53 as a yellow oil. Purification of the residue by means of flash
column chromatography (Al2O3 grade V, petroleum ether/Et2O, 1:1) fur-
nished 53 as a yellow oil (47 mg, 10%,>99:1 d.r.); 1H NMR (400 MHz,
CDCl3): d=1.10 (3H, d, J=6.7 Hz, C(2)CH3), 2.22 (3H, s, NCH3), 2.78
(1H, qd, J=6.7, 6.4 Hz, C(2)H), 3.50 (1H, d, J=13.2 Hz, NCHA), 3.55
(1H, d, J=13.2 Hz, NCHB), 3.81 (3H, s, OCH3), 4.35 (1H, d, J=6.4 Hz,
C(1)H), 5.22–5.54 (5H, m, ArCr(CO)3), 6.79–7.07 ppm (4H, m, Ar); MS
(CI): m/z: 422 ([M+H]+, 100%).
ACHTUNGTRENNUNG
A
9.40 mmol) in CH2Cl2 (50 mL) was cyclized according to general proce-
dure 3 at 408C for 3.25 h to give a 94:6 mixture of 43 and 48, respectively.
Purification by means of flash column chromatography (eluent Et2O)
gave an inseparable 94:6 mixture of 43 and 48 as a colourless oil (2.23 g,
quant); IR (film): n˜max =3005, 1485, 700 cmÀ1; MS (CI): m/z: 237 ([M]+,
100%); elemental analysis: calcd (%) for C17H19N: C 86.0; H 8.1; N 5.9;
found: C 85.7; H 8.2; N 6.3.
ACHTUNGTRENNUNG(1R,2S)-1-Phenyl-2-[N-methyl-N-(tert-butoxycarbonyl)amino]propan-1-ol
(49): A solution of (1R,2S)-ephedrine 19 (20.0 g, 121 mmol) in CH2Cl2
(400 mL) at 08C was treated with Boc2O (33.7 g, 139 mmol) and NEt3
(16.8 mL, 121 mmol) and the resultant solution was left to stand at 208C
for 60 h. Saturated aqueous citric acid (500 mL) was then added to the
reaction mixture, and the organic phase was separated and washed se-
quentially with sat aq NaHCO3 (500 mL), water (500 mL) and brine
(500 mL) then dried, filtered and concentrated in vacuo. Purification of
the residue by means of reduced pressure distillation (1608C,
AHCTUNGTERG{NNUN (1R,2S)-1-Phenyl-2-[N-methyl-N-(3’-methoxybenzyl)amino]propan-1-ol}-
tricarbonylchromium(0) (54): A mixture of 51 (620 mg, 2.06 mmol) and
freshly distilled 3-methoxybenzylbromide (500 mg, 2.49 mmol) in EtOH
(10 mL) was reacted according to general procedure 1 in the presence of
NaHCO3 (260 mg, 3.09 mmol) and a catalytic quantity of NaI at RT for
19.5 h to give a yellow oil. Purification of the residue by means of flash
column chromatography (Al2O3 grade V, gradient elution petroleum
ether/Et2O) gave 54 as a yellow oil (427 mg, 49%,>99:1 d.r.); 1H NMR
(400 MHz, CDCl3): d=1.12 (3H, d, J=6.7 Hz, C(2)CH3), 2.24 (3H, s,
NCH3), 2.73 (1H, d, J=3.0 Hz, OH), 2.78 (1H, app quin, J=6.7 Hz,
C(2)H), 3.53 (1H, d, J=13.5 Hz, NCHA), 3.58 (1H, d, J=13.5 Hz,
NCHB), 3.80 (3H, s, OCH3), 4.35 (1H, dd, J=6.7 Hz, 3.0, C(1)H), 5.22–
5.54 (5H, m, ArCr(CO)3), 6.70–7.21 ppm (4H, m, Ar); MS (CI): m/z: 422
([M+H]+, 100%).
0.06 mmHg) gave 49 as a colourless oil (27.3 g, 85%,>99:1 d.r.); [a]D20
=
À26.8 (c=1.9 in CHCl3); IR (film): n˜max =3420, 3008, 1675, 703 cmÀ1
;
1H NMR (400 MHz, [D6]DMSO, 360 K): d=1.17 (3H, d, J=6.9 Hz,
C(2)CH3), 1.30 (9H, s, CACHTNUTGRNEN(UG CH3)3), 2.64 (3H, s, NCH3), 4.06 (1H, app quin,
J=7.0 Hz, C(2)H), 4.57 (1H, dd, J=7.0, 5.0 Hz, C(1)H), 5.17 (1H, d, J=
5.0 Hz, OH), 7.18–7.34 ppm (5H, m, Ph); 13C NMR (100 MHz, CDCl3):
d=12.8, 28.2, 31.8, 58.1, 76.7, 79.7, 126.4, 127.6, 128.2, 142.3, 142.4 ppm;
MS (CI): m/z: 266 ([M+H]+, 100%); elemental analysis: calcd (%) for
C15H23NO3: C 67.9, H 8.7, N 5.3; found: C 68.2, H 9.0, N 5.2.
AHCTUNGTERG{NNUN (1R,2S)-1-Phenyl-2-[N-methyl-N-(2’-methoxybenzyl)amino]propan-1-ol}-
tricarbonylchromium(0) (55): A mixture of 51 (176 mg, 0.58 mmol) and
freshly distilled 2-methoxybenzylbromide (127 mg, 0.63 mmol) in EtOH
(5 mL) was reacted according to general procedure 1 in the presence of
NaHCO3 (67 mg, 0.80 mmol) and a catalytic quantity of NaI at RT for
63 h to furnish 55 as a yellow oil (111 mg, 45%,>99:1 d.r.). Crystalliza-
tion of an aliquot (Et2O/hexane) gave an analytically pure sample of 55;
ACHTUNGTRENNUNG{(1R,2S)-1-Phenyl-2-[N-methyl-N-(tert-butoxycarbonyl)amino]propan-1-
ol}tricarbonylchromium(0) (50): A deoxygenated mixture of 49 (20.1 g,
75.8 mmol) and Cr(CO)6 (16.7 g, 75.9 mmol) in Bu2O (400 mL) and THF
(40 mL) was heated at reflux under a nitrogen atmosphere for 48 h.[26]
The resultant mixture was allowed to cool to RT, filtered and concentrat-
ed in vacuo. Purification of the residue by means of recrystallization
(CH2Cl2/hexane) gave 50 as a yellow powder (16.5 g, 54%,>99:1 d.r.);
m.p.: 848C; [a]2D0 =À36.2 (c=0.1 in CHCl3); IR (KBr disc): n˜max =1965,
1
[a]D22 =+28.8 (c 0.1 in CHCl3); IR (film): n˜max =1965, 1885 cmÀ1; H NMR
(400 MHz, CDCl3): d=1.07 (3H, d, J=6.8 Hz, C(2)CH3), 2.19 (3H, s,
NCH3), 2.83 (1H, qd, J=6.8, 5.4 Hz, C(2)H), 3.65 (1H, d, J=3.3 Hz,
OH), 3.57 (1H, d, J=13.2 Hz, NCHA), 3.69 (1H, d, J=13.2 Hz, NCHB),
3.87 (3H, s, OCH3), 4.49 (1H, br s, C(1)H), 5.18–5.60 (5H, m,
ArCr(CO)3), 6.88–7.29 ppm (4H, m, Ar); MS (CI): m/z: 421 ([M]+,
100%); elemental analysis: calcd (%) for C21H23CrNO5: C 59.85, H 5.5,
N 3.3; found: C 59.65, H 5.6, N 3.1.
1885, 1668 cmÀ1
;
1H NMR (400 MHz, [D6]DMSO, 360 K): d=1.17 (3H,
d, J=6.9 Hz, C(2)CH3) 1.34 (9H, s, CACTHNUGTNRE(NUG CH3)3), 2.72 (3H, s, NCH3), 3.93
(1H, app q, J=6.9 Hz, C(2)H), 4.21 (1H, app t, J=6.9 Hz, C(1)H), 5.47–
5.77 ppm (5H, m, ArCr(CO)3); MS (CI): m/z: 402 ([M+H]+, 100%); ele-
mental analysis: calcd (%) for C18H23CrNO6: C 53.9, H 5.8, N 3.5; found:
C 54.2, H 6.0, N 3.2.
AHCTUNGTERG[NNUN (1R,2S)-1-Phenyl-2-(N-methyl-N-benzylamino)propan-1-ol]tricarbonyl-
A
chromium(0) (56): A mixture of [(ephedrine)Cr(CO)3] (51) (792 mg,
2.63 mmol) and BnBr (0.35 mL, 2.94 mmol) in EtOH (10 mL) was react-
600
www.chemasianj.org
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Asian J. 2010, 5, 589 – 604

Cyclization of Substituted N-Benzylethanolamines
ed according to general procedure 1 in the presence of NaHCO3 (331 mg,
3.94 mmol) and a catalytic quantity of NaI at RT for 68 h to give 56 as a
yellow oil (653 mg, 63%,>99:1 d.r.); 1H NMR (400 MHz, CDCl3): d=
1.12 (3H, d, J=6.7 Hz, C(2)CH3), 2.24 (3H, s, NCH3), 2.78 (1H, app
quin, J=6.7 Hz, C(2)H), 3.56 (1H, d, J=13.5 Hz, NCHA), 3.61 (1H, d,
J=13.5 Hz, NCHB), 4.36 (1H, d, J=6.7 Hz, C(1)H), 5.22–5.53 (5H, m,
ArCr(CO)3), 7.12–7.40 ppm (5H, m, Ph).
NCHA), 3.65 (1H, d, J=12.8 Hz, NCHB), 3.82 (3H, s, OCH3), 3.90 (1H,
d, J=9.6 Hz, C(1)H), 5.14 (1H, br s, OH), 5.21–5.53 (5H, m,
ArCr(CO)3), 6.86–7.24 ppm (4H, m, Ar); MS (CI): m/z: 422 ([M+H]+,
100%); elemental analysis: calcd (%) for C21H23CrNO5: C 59.85, H 5.5,
N 3.3; found: C 60.0, H 5.8, N 3.2.
AHCTUNGTERG{NNUN (1R,2R)-1-Phenyl-2-[N-methyl-N-(3’-methoxybenzyl)amino]propan-1-
ol}tricarbonylchromium(0) (61): A mixture of 58 [freshly prepared from
57] (510 mg, 1.34 mmol) and 3-methoxybenzaldehyde (190 mg,
1.40 mmol) in CH2Cl2 (25 mL) was reacted according to general proce-
dure 2 to give the corresponding oxazolidine as a yellow oil (332 mg,
59%). This material was reduced with NaBH3CN (84 mg, 1.34 mmol) to
give 61 as a yellow solid (60 mg, 40%,>99:1 d.r.). Purification of an ali-
quot by means of recrystallization (CH2Cl2/hexane) gave an analytically
pure sample of 61 as a yellow crystalline solid; m.p.: 118–1198C (CH2Cl2/
hexane); [a]2D2 =+82.2 (c=0.1 in CHCl3); IR (KBr disc): n˜max =3020,
ACHTUNGTRENNUNG
A
60.5 mmol) and cyclohexanone (10.0 mL, 96.5 mmol) in C6H6 (100 mL)
was heated at reflux in a Dean–Stark apparatus for 22 h. The reaction
mixture was then concentrated in vacuo and the residue was distilled
under reduced pressure (1668C, 0.06 mm Hg) to give (4S,5R)-2-cyclohex-
yl-N(3),4-dimethyl-5-phenyloxazolidine as a colourless oil that solidified
on standing (13.6 g, 91%); m.p.: 72–738C (m.p.: 77–788C[28]); [a]D20
=
+9.53 (c=1.2 in CHCl3) {[a]2D0 =+8.0 (c=1.0 in CHCl3)[27]}; 1H NMR
(400 MHz, CDCl3): d=0.63 (3H, d, J=6.4 Hz, C(4)CH3) 1.75–1.13 (10H,
m, (CH2)5), 2.30 (3H, s, NCH3), 3.25 (1H, dq, J=8.0, 6.4 Hz, C(4)H),
5.07 (1H, d, J=8.0 Hz, C(5)H), 7.34–7.22 ppm (5H, m, Ph). A deoxygen-
ated solution of this material (3.00 g, 12.2 mmol) and Cr(CO)6 (3.00 g,
13.6 mmol) in Bu2O (50 mL) and THF (4 mL) was heated at reflux under
a nitrogen atmosphere for 48 h.[26] The resultant mixture was allowed to
cool to RT, filtered and concentrated in vacuo. Purification of the residue
by means of recrystallization (CH2Cl2/hexane) gave 57 as a yellow solid
(1.98 g, 42%); m.p.: 1078C (CH2Cl2/hexane); [a]2D0 =+156 (c=0.3 in
1972, 1890 cmÀ1; H NMR (400 MHz, CDCl3): d=1.01 (3H, d, J=6.6 Hz,
1
C(2)CH3), 2.22 (3H, s, NCH3), 2.59 (1H, dq, J=9.5, 6.6 Hz, C(2)H), 3.48
(1H, d, J=13.0 Hz, NCHA), 3.69 (1H, d, J=13.0 Hz, NCHB), 3.83 (3H, s,
OCH3), 3.92 (1H, d, J=9.5 Hz, C(1)H), 5.08 (1H, br s, OH), 5.22–5.54
(5H, m, ArCr(CO)3), 6.81–7.29 ppm (4H, m, Ar); MS (CI): m/z: 422
([M+H]+, 100%); elemental analysis: calcd (%) for C21H23CrNO5:
C 59.85, H 5.5, N 3.3; found: C 59.6, H 5.6, N 3.3.
AHCTUNGTERG{NNUN (1R,2R)-1-Phenyl-2-[N-methyl-N-(2’-methoxybenzyl)amino]propan-1-
ol}tricarbonylchromium(0) (62): A mixture of 58 [freshly prepared from
57] (146 mg, 0.38 mmol) and 2-methoxybenzaldehyde (60 mg, 0.44 mmol)
in CH2Cl2 (5 mL) was reacted according to general procedure 2 to give
the corresponding oxazolidine as a yellow oil. Without further purifica-
tion, this material was reduced with NaBH4 (15 mg, 0.38 mmol) to give,
after purification by means of recrystallization (CH2Cl2/hexane), 62 as a
yellow solid (21 mg, 13%,>99:1 d.r.); m.p.: 124–1258C (CH2Cl2/hexane);
[a]2D2 =+68.2 (c=0.05 in CHCl3); IR (KBr disc): n˜max =3020, 1970,
CHCl3); IR (KBr disc): n˜max =1973, 1890 cmÀ1 1H NMR (400 MHz,
;
CDCl3): d=0.83 (3H, d, J=6.4 Hz, C(4)CH3), 1.89–1.09 (10H, m,
(CH2)5), 2.26 (3H, s, NCH3), 3.20 (1H, dq, J=8.0, 6.4 Hz, C(4)H), 4.57
(1H, d, J=8.0 Hz, C(5)H), 5.57–5.13 ppm (5H, m, Ar); MS (CI): m/z:
381 ([M]+, 100%); elemental analysis: calcd (%) for C19H23CrNO4:
C 59.8, H 6.1, N 3.7; found: C 59.55, H 6.2, N 3.8.
A
1895 cmÀ1 1H NMR (400 MHz, CDCl3): d=1.02 (3H, d, J=6.7 Hz,
;
um(0) (58): A solution of 57 (302 mg, 0.79 mmol) and TsOH (103 mg,
0.54 mmol) in THF (10 mL) and water (5 mL) was treated with HCl
(conc aq, 1 mL) and the resultant mixture was heated at reflux for 15 h.
The reaction mixture was then allowed to cool to RT then basified with
2.0m aq NaOH (20 mL), the solvent evaporated and the aqueous phase
was extracted with Et2O (20 mL). The combined organic extracts were
dried, filtered, and concentrated in vacuo to give 58 (238 mg, quant).
C(2)CH3), 2.19 (3H, s, NCH3), 2.58 (1H, dq, J=9.5, 6.7 Hz, C(2)H), 3.44
(1H, d, J=12.6 Hz, NCHA), 3.75 (1H, d, J=12.6 Hz, NCHB), 3.87 (3H, s,
OCH3), 3.93 (1H, d, J=9.5 Hz, C(1)H), 5.21–5.55 (5H, m, ArCr(CO)3),
6.89–7.32 ppm (4H, m, Ar); MS (CI): m/z: 422 ([M+H]+, 100%);
+
HRMS (CI+) C19H23CrNO3 ([M-C2O2]+) requires 365.1078; found
365.1077.
AHCTUNGTRENNUNG
A
A
1-ol}tricarbonylchromium(0) (59): A mixture of 58 [freshly prepared
from 57] (260 mg, 0.54 mmol) and freshly distilled 3,4-dimethoxybenzyl-
bromide (128 mg, 0.55 mmol) in MeCN (40 mL) was reacted according to
general procedure 1 for 3 h to give a yellow oil. Purification of the resi-
due by means of flash column chromatography (Al2O3 grade V, eluent
Et2O) gave 59 as a yellow solid (149 mg, 61%,>99:1 d.r.). Purification of
an aliquot by means of recrystallization (CH2Cl2/hexane) gave an analyti-
cally pure sample of 59; m.p.: 124–1288C (CH2Cl2/hexane); [a]2D0 =+83.7
0.38 mmol) and BnBr (50 mL, 0.42 mmol) in EtOH (10 mL) was reacted
according to general procedure 1 in the presence of NaHCO3 (50 mg,
0.60 mmol) and a catalytic quantity of NaI at RT for 71 h. Purification of
the residue by means of recrystallization (CH2Cl2/hexane) gave 63 as a
yellow solid (40 mg, 27%,>99:1 d.r.); m.p.: 1598C (CH2Cl2/hexane);
[a]D22 =+80.0 (c=0.1 in CHCl3); IR (film): n˜max =3020, 1972, 1895 cmÀ1
;
1H NMR (400 MHz, CDCl3): d=1.01 (3H, d, J=6.7 Hz, C(2)CH3), 2.21
(3H, s, NCH3), 2.59 (1H, dq, J=9.5, 6.7 Hz, C(2)H), 3.50 (1H, d, J=
12.9 Hz, NCHA), 3.72 (1H, d, J=12.9 Hz, NCHB), 3.92 (1H, d, J=9.5 Hz,
C(1)H), 5.12 (1H, br s, OH), 5.22–5.53 (5H, m, ArCr(CO)3), 7.29–
7.38 ppm (5H, m, Ph); MS (CI): m/z: 392 ([M+H]+, 100%); elemental
analysis: calcd (%) for C20H21CrNO4: C 61.4, H 5.4; found: C 61.25,
H 5.5.
(c=0.1 in CHCl3); IR (KBr disc): n˜max =1975, 1885 cmÀ1 1H NMR
;
(400 MHz, CDCl3): d=1.00 (3H, d, J=6.7 Hz, C(2)CH3), 2.21 (3H, s,
NCH3), 2.58 (1H, dq, J=9.0, 6.7 Hz, C(2)H), 3.44 (2H, d, J=12.8 Hz,
NCHA), 3.67 (1H, d, J=12.8 Hz, NCHB), 3.89 (3H, s, OCH3), 3.90 (3H,
s, OCH3), 3.97 (1H, d, J=9.0 Hz, C(1)H), 5.14 (1H, br s, OH), 5.22–5.52
(5H, m, ArCr(CO)3), 6.82–6.84 ppm (3H, m, Ar); MS (CI): m/z: 452
([M+H]+, 100%); elemental analysis: calcd (%) for C22H25CrNO6:
C 58.5, H 5.6, N 3.1; found: C 58.5, H 5.8, N 3.0.
AHCTUNGTERG(NNUN 3R,4S)-N(2),3-Dimethyl-4-phenyl-6,7-dimethoxy-1,2,3,4-tetrahydroiso-
quinoline (39): A solution of 59 (100 mg, 0.22 mmol) in CH2Cl2 (15 mL)
was reacted according to general procedure 4 at 08C for 2 h to give a
yellow oil (>99:1 d.r. crude). Purification of the residue by means of
flash column chromatography (Al2O3 grade V, eluent CH2Cl2) gave
[(3R,4S)-N(2),3-dimethyl-4-phenyl-6,7-dimethoxy-1,2,3,4-tetrahydroiso-
ACHTUNGTRENNUNG{(1R,2R)-1-Phenyl-2-[N-methyl-N-(4’-methoxybenzyl)amino]propan-1-
ol}tricarbonylchromium(0) (60): A mixture of 58 [freshly prepared from
57] (1.09 g, 2.85 mmol) and 4-methoxybenzaldehyde (700 mg, 5.14 mmol)
in CH2Cl2 (20 mL) was reacted according to general procedure 2 to fur-
nish the corresponding oxazolidine as a yellow oil after purification by
flash column chromatography (Al2O3 grade V, eluent Et2O). This materi-
al was reduced with NaBH4 (108 mg, 2.85 mmol) to give, after purifica-
tion by means of recrystallization (CH2Cl2/hexane), 60 as a yellow solid
(72 mg, 6%,>99:1 d.r.); m.p.: 154–1558C (CH2Cl2/hexane); [a]2D2 =+91.6
quinoline]tricarbonylchromium(0) as
a
yellow oil (99 mg, quant,
>99:1 d.r.); 1H NMR (400 MHz, CDCl3): d=1.01 (3H, d, J=6.5 Hz,
C(3)CH3) 2.34 (3H, s, NCH3), 3.12 (1H, q, J=6.5 Hz, C(3)H), 3.44 (1H,
app s, C(4)H), 3.44 (1H, d, J=15.6 Hz, C(1)HA), 3.70 (1H, d, J=15.6 Hz,
C(1)HB), 3.88 (3H, s, OCH3), 3.91 (3H, s, OCH3), 4.87–5.71 (5H, m,
ArCr(CO)3), 6.56 (1H, s, C(5)H), 6.91 ppm (1H, s, C(8)H); MS (CI):
m/z: 434 ([M+H]+, 100%). This material was decomplexed according to
general procedure 5 to give 39 as a colourless oil (64 mg, 95% for 2
steps,>99:1 d.r.); [a]2D0 =+13.8 (c=0.2 in CHCl3); MS (CI): m/z: 297
(c=0.1 in CHCl3); IR (KBr disc): n˜max =3010, 1975, 1890 cmÀ1 1H NMR
;
(400 MHz, CDCl3): d=0.99 (3H, d, J=6.6 Hz, C(2)CH3), 2.19 (3H, s,
NCH3), 2.58 (1H, dq, J=9.6, 6.6 Hz, C(2)H), 3.43 (1H, d, J=12.8 Hz,
Chem. Asian J. 2010, 5, 589 – 604
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemasianj.org
601

S. G. Davies et al.
FULL PAPERS
+
([M]+, 100%); HRMS (CI+) C19H23NO2 ([M]+) requires 297.1723;
found 297.1728.
C(1)HA), 3.91 (1H, d, J=15.1 Hz, C(1)HB), 4.02 (1H, d, J=4.4 Hz,
C(4)H), 6.42 (1H, s, C(5)H), 6.57 (2H, s, C(8)H), 7.17–7.29 ppm (5H, m,
Ph); 13C NMR (100 MHz, CDCl3): d=14.4, 42.3, 50.8, 55.9, 56.6, 59.2,
108.6, 112.4, 126.1, 126.9, 127.6, 128.2, 129.5, 130.4, 142.8, 147.5,
ACHTUNGTRENNUNG(3R,4S)-N(2),3-Dimethyl-4-phenyl-6-methoxy-1,2,3,4-tetrahydroisoquino-
line (40): A solution of 60 (44 mg, 0.10 mmol) in CH2Cl2 (10 mL) was cy-
clized according to general procedure 4 at À208C for 24 h to give
[(3R,4S)-N(2),3-dimethyl-4-phenyl-6-methoxy-1,2,3,4-tetrahydroisoquino-
line]-tricarbonylchromium(0) as a yellow oil (40 mg, 95%,>99:1 d.r.).
This material (40 mg, 0.10 mmol) was decomplexed according to general
procedure 5 to give, after purification by means of recrystallization
(Et2O/hexane), 40 as a white solid (25 mg, 94%,>99:1 d.r.); m.p.: 758C
(Et2O/hexane); [a]2D0 =+4.3 (c=0.4 in CHCl3).
+
147.6 ppm; MS (CI): m/z: 297 ([M]+, 100%); HRMS (CI+) C19H23NO2
([M]+) requires 297.1723; found 297.1728.
AHCTUNGTERG(NNUN 3S,4R)-2,3-Dimethyl-4-phenyl-6-methoxy-1,2,3,4-tetrahydroisoquinoline
(40): A solution of 53 (47 mg, 0.11 mmol) in CH2Cl2 (15 mL) was cyclized
according to general procedure 4 at À208C for 46 h to give [(3S,4R)-2,3-
dimethyl-4-phenyl-6-methoxy-1,2,3,4-tetrahydroisoquinoline]-tricarbonyl-
chromium(0) as
a
yellow solid (42 mg, 93%,>99:1 d.r.); 1H NMR
(400 MHz, CDCl3): d=1.00 (3H, d, J=6.7 Hz, C(3)CH3), 2.37 (3H, s,
NCH3), 3.17 (1H, app q, J=6.7 Hz, C(3)H), 3.45 (1H, app s, C(4)H),
3.46 (1H, d, J=15.5 Hz, C(1)HA), 3.73 (1H, d, J=15.5 Hz, C(1)HB), 3.83
(3H, s, OCH3), 4.94–5.83 (5H, m, ArCr(CO)3), 6.81 (1H, dd, J=8.5,
2.6 Hz, C(7)H), 6.92 (1H, d, J=2.5 Hz, C(5)H), 7.00 ppm (1H, d, J=
8.5 Hz, C(8)H); MS (CI): m/z: 403 ([M]+, 100%); HRMS (CI+)
ACHTUNGTRENNUNG(3R,4S)-N(2),3-Dimethyl-4-phenyl-8-methoxy-1,2,3,4-tetrahydroisoquino-
line (42): A solution of 62 (44 mg, 0.10 mmol) in CH2Cl2 (10 mL) was cy-
clized according to general procedure 4 at À208C for 24 h to give
[(3R,4S)-N(2),3-dimethyl-4-phenyl-8-methoxy-1,2,3,4-tetrahydroisoquino-
line]-tricarbonylchromium(0) as
a yellow oil. This material (40 mg,
0.10 mmol) was decomplexed according to general procedure 5 to give,
after purification by means of recrystallization (Et2O/hexane), 40 as a
white solid (4 mg, 9%,>99:1 d.r.); m.p.: 114–1168C (Et2O/hexane);
[a]2D0 =+63 (c=1.0 in CHCl3).
+
C21H21CrNO4 ([M]+) requires 403.0876; found 403.0880. This material
(42 mg, 0.10 mmol) was decomplexed according to general procedure 5 to
furnish, after purification by means of recrystallization (Et2O/hexane), 40
as a white solid (23 mg, 84%, >99:1 d.r.); m.p.: 758C (Et2O/hexane);
[a]2D0 =À3.9 (c=0.5 in CHCl3).
(RS)-N-Methyl-N-(2’-methoxybenzyl)-1-phenyl-propan-2-amine
(64):
(RS)-N-(Methyl)amphetamine hydrochloride (1.77 g, 9.54 mmol) was dis-
solved in excess 2.0m aq NaOH and the resultant solution was extracted
with CH2Cl2 (3ꢂ50 mL). The combined organic extracts were dried, fil-
tered and concentrated in vacuo to give (RS)-N-(methyl)amphetamine as
a colourless oil (1.41 g, 99%). A mixture of this material and freshly dis-
tilled 2-methoxybenzylbromide (1.92 g, 9.54 mmol) in MeCN (50 mL)
was reacted according to general procedure 1 to give (RS)-64 as a pale
yellow oil (2.45 g, 96%). Purification of an aliquot by means of reduced
pressure bulb-to-bulb distillation (b.p.: ꢁ1808C, 0.06 mm Hg) gave an
analytically pure sample of (RS)-64; IR (film): n˜max =3010, 1492,
AHCTUNGTERG(NNUN 3S,4R)-N(2),3-Dimethyl-4-phenyl-8-methoxy-1,2,3,4-tetrahydroisoquino-
line (42) and (S)-N-methyl-N-(2’-methoxybenzyl)-1-phenyl-propan-2-
amine (64): A solution of 55 (66 mg, 0.16 mmol) in CH2Cl2 (20 mL) was
reacted according to general procedure 4 at À208C for 36 h, followed by
decomplexation according to general procedure 5 gave a 63:37 mixture of
42 and 64 as a yellow oil (38 mg, 90% from 55 in 2 steps). Purification of
the residue by means of recrystallization (Et2O/hexane) gave an analyti-
cally pure sample of 42 (21 mg, 50%,>99:1 d.r.); m.p.: 1158C; [a]D20
=
À66.4 (c=0.1 in CHCl3). The mother liquor was concentrated in vacuo
and the residue was purified by flash column chromatography (eluent
Et2O) to give 64 as a colourless oil (17 mg, 31%).
700 cmÀ1
;
1H NMR (400 MHz, CDCl3): d=1.04 (3H, d, J=6.5 Hz,
C(3)H3), 2.32 (3H, s, NCH3), 2.50–3.12 (3H, m, C(1)H2, C(2)H), 3.64
(1H, d, J=14.1 Hz, NCHA), 3.67 (1H, d, J=14.1 Hz, NCHB), 3.85 (3H, s,
OCH3), 6.86–7.34 ppm (9H, m, Ph, Ar); 13C NMR (100 MHz, CDCl3):
d=14.0, 37.5, 39.4, 50.9, 55.3, 60.6, 110.3, 120.4, 125.8, 127.8, 128.2, 128.3,
129.4, 130.3, 141.2, 157.9 ppm; MS (CI): m/z: 270 ([M+H]+, 100%); ele-
mental analysis: calcd (%) for C18H23NO: C 80.3, H 8.6, N 5.2; found:
C 80.2, H 8.8, N 5.1.
(S)-N-methyl-N-benzyl-1-phenyl-propan-2-amine (65): A solution of 56
(319 mg, 0.82 mmol) in CH2Cl2 (20 mL) was treated according to general
procedure 4 at À208C for 48 h, followed by decomplexation according to
general procedure 5 to give 65 as a colourless oil (78 mg, 40% from 56 in
2
steps); 1H NMR (400 MHz, CDCl3): d=1.04 (3H, d, J=6.5 Hz,
C(3)H3), 2.28 (3H, s, NCH3), 2.39–3.10 (3H, m, C(1)H2, C(2)H), 3.62
(2H, brs, NCH2), 7.11–7.44 ppm (10H, m, Ph); MS (CI): m/z: 240
([M+H]+, 100%).
ACHTUNGTRENNUNG(3R,4S)-N(2),3-Dimethyl-4-phenyl-1,2,3,4-tetrahydroisoquinoline (43): A
solution of 63 (29 mg, 0.07 mmol) in CH2Cl2 (6 mL) was reacted accord-
ing to general procedure 4 at À208C for 24.5 h, followed by decomplexa-
tion according to general procedure 5 to give 43 as a yellow oil (18 mg,
89% from 63 in 2 steps). Purification of the residue by means of flash
column chromatography (eluent Et2O) gave 43 as a colourless oil (6 mg,
28%,>99:1 d.r.); [a]2D0 =+47 (c=0.1 in CHCl3).
AHCTUNGTERG(NNUN 3R,4S)-N(2),3-Dimethyl-4-phenyl-7-methoxy-1,2,3,4-tetrahydroisoquino-
line (41) and (3R,4S)-N(2),3-dimethyl-4-phenyl-5-methoxy-1,2,3,4-tetra-
hydroisoquinoline] (68): A solution of 61 (51 mg, 0.12 mmol) in CH2Cl2
(5 mL) was reacted according to general procedure 4 at À208C for 42 h
to give an inseparable 91:9 mixture of 66 and 67 as a yellow oil (40 mg,
74%). This material (36 mg, 0.09 mmol) was decomplexed according to
general procedure 5 to give an inseparable 91:9 mixture of 41 and 68
ACHTUNGTRENNUNG(3S,4S)-N(2),3-Dimethyl-4-phenyl-6,7-dimethoxy-1,2,3,4-tetrahydroisoqui-
noline (44): A solution of 52 (61 mg, 0.14 mmol) in CH2Cl2 (5 mL) was
cyclized according to general procedure 4 at À208C for 43 h to give
(crude>99:1 d.r.), after purification by flash column chromatography
(Al2O3 grade V, eluent Et2O), [(3S,4S)-N(2),3-dimethyl-4-phenyl-6,7-di-
1
(21 mg, 88%). Data for 68: H NMR (400 MHz, CDCl3): d=1.00 (3H, d,
J=6.6 Hz, C(3)CH3), 2.38 (3H, s, NCH3), 3.21 (1H, q, J=6.5 Hz,
C(3)H), 3.42 (1H, s, C(4)H), 3.50 (1H, d, J=16.2 Hz, C(1)HA), 3.74 (1H,
d, J=16.2 Hz, C(1)HB), 3.80 (3H, s, OCH3), 4.95–5.86 (5H, m,
ArCr(CO)3), 6.61 (1H, d, J=2.7 Hz, C(8)H), 6.82 (1H, dd, J=8.5,
2.7 Hz, C(6)H), 7.27 ppm (1H, d, J=8.5 Hz, C(5)H); MS (CI): m/z: 404
([M+H]+, 100%).
methoxy-1,2,3,4-tetrahydroisoquinoline]tricarbonyl-chromium(0) as
a
yellow solid (48 mg, 82%,>99:1 d.r.). Further purification of an aliquot
by means of recrystallization (CH2Cl2/hexane) gave an analytically pure
sample (>99:1 d.r.); [a]D20 =+173 (c=0.2 in CHCl3); IR (film): n˜max
=
1965, 1885 cmÀ1; H NMR (400 MHz, CDCl3): d=1.06 (3H, d, J=6.8 Hz,
C(3)CH3), 2.28 (3H, s, NCH3), 2.76 (1H, qd, J=6.8, 3.2 Hz, C(3)H), 3.46
(1H, d, J=3.2 Hz, C(4)H), 3.87 (3H, s, OCH3), 3.93 (3H, s, OCH3), 3.40
(1H, d, J=15.2 Hz, C(1)HA), 3.94 (1H, d, J=15.2 Hz, C(1)HB), 5.06–5.63
(5H, m, ArCr(CO)3), 6.52 ppm (2H, s, C(5)H), 7.03 (2H, s, C(8)H); MS
(CI): m/z: 434 ([M+H]+, 100%); elemental analysis: calcd (%) for
C22H23CrNO5: C 61.0, H 5.35, N 3.2; found: C 61.0, H 5.6, N 3.5. This ma-
terial (48 mg, 0.11 mmol) was decomplexed according to general proce-
ACHTUNGTNER(NUNG 3S,4S)-N(2),3-Dimethyl-4-phenyl-7-methoxy-1,2,3,4-tetrahydroisoquino-
1
line (46) and (3S,4S)-N(2),3-dimethyl-4-phenyl-5-methoxy-1,2,3,4-tetrahy-
droisoquinoline (71): A solution of 54 (427 mg, 1.01 mmol) in CH2Cl2
(25 mL) was reacted according to general procedure 4 at À208C for 142 h
to give an 86:14 mixture of regioisomeric cis-tetrahydroisoquinolines as a
yellow oil. Purification of the residue by means of flash column chroma-
tography (Al2O3 grade V, petroleum ether/Et2O, 8:1) gave [(3S,4S)-
N(2),3-dimethyl-4-phenyl-5-methoxy-1,2,3,4-tetrahydroisoquinoline]tri-
carbonylchromium(0) as yellow oil (32 mg, 8%,>99:1 d.r.); [a]2D0 =+9.4
dure 5 to give 44 as a white powder (30 mg, 92%,>99:1 d.r.); [a]D20
+108 (c=0.1 in CHCl3); m.p.: 93–948C (CH2Cl2/hexane); IR (KBr disc):
n˜max =3010, 1520, 705 cmÀ1 1H NMR (400 MHz, CDCl3): d=0.83 (3H, d,
=
(c=0.1 in CHCl3); IR (film): n˜max =1966, 1890 cmÀ1 1H NMR (400 MHz,
;
CDCl3): d=1.01 (3H, d, J=6.7 Hz, C(3)CH3), 2.25 (3H, s, NCH3), 2.61
(1H, qd, J=6.7, 2.6 Hz, C(3)H), 3.67 (1H, d, J=2.6 Hz, C(4)H), 3.89
(3H, s, OCH3), 3.43 (1H, d, J=16.0 Hz, C(1)HA), 4.11 (1H, d, J=
;
J=6.6 Hz, C(3)CH3), 2.38 (3H, s, NCH3), 2.85 (1H, dq, J=6.6, 4.4 Hz,
C(3)H), 3.68 (3H, s, OCH3), 3.86 (3H, s, OCH3), 3.48 (1H, d, J=15.1 Hz,
602
www.chemasianj.org
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Asian J. 2010, 5, 589 – 604

Cyclization of Substituted N-Benzylethanolamines
16.0 Hz, C(1)HB), 4.89–5.73 (5H, m, ArCr(CO)3), 6.70–6.77 (2H, m,
C(6)H, C(8)H), 7.21 ppm (1H, app t, J=7.9 Hz, C(7)H); MS (CI): m/z:
403 ([M]+, 100%); elemental analysis: calcd (%) for C21H21CrNO4:
C 62.5, H 5.25, N 3.5; found: C 62.6, H 5.3, N 3.2. Further elution gave
[(3S,4S)-N(2),3-dimethyl-4-phenyl-7-methoxy-1,2,3,4-tetrahydroisoquino-
line]tricarbonylchromium(0) as a yellow oil (205 mg, 50%,>99:1 d.r.);
1H NMR (400 MHz, CDCl3): d=1.07 (3H, d, J=6.8 Hz, C(3)CH3), 2.28
(3H, s, NCH3), 2.76 (1H, dq, J=6.8, 3.3 Hz, C(3)H), 3.50 (1H, d, J=
3.3 Hz, C(4)H), 3.80 (3H, s, OCH3), 3.44 (1H, d, J=15.7 Hz, C(1)HA),
3.98 (1H, d, J=15.7 Hz, C(1)HB), 5.02–5.63 (5H, m, ArCr(CO)3), 6.58
(1H, d, J=2.6 Hz, C(8)H), 6.84 (1H, dd, J=8.6, 2.6 Hz, C(6)H),
7.42 ppm (1H, d, J=8.6 Hz, C(5)H); MS (CI): m/z: 403 ([M]+, 100%);
[8] W. L. Mendelson, C. B. Spainhour, S. S. Jones, B. L. Lam, K. L.
Wert, Tetrahedron Lett. 1980, 21, 1393; M. R. Euerby, R. D. Waigh,
J. Chem. Soc. Chem. Commun. 1984, 127.
[9] L. N. Pridgen, L. B. Killmer, R. L. Webb, J. Org. Chem. 1982, 47,
1985.
[10] The direct asymmetric synthesis of enantiopure 4-aryl-tetrahydroiso-
quinolines has received far less attention from the synthetic com-
munity, although a limited number have been prepared by classical
resolution procedures. See ref. [4] within.
[11] For reviews, see: S. G. Davies, T. J. Donohoe, Synlett 1993, 323; S. G.
Davies, J. Organomet. Chem. 1990, 400, 223. For theoretical work on
chromium tricarbonyl chemistry, see for example: C. A. Merlic, J. C.
Walsh, D. J. Tantillo, K. N. Houk, J. Am. Chem. Soc. 1999, 121,
3596–3606; A. Pfletschinger, T. K. Dargel, J. W. Bats, H.-G.
Schmalz, W. Koch, Chem. Eur. J. 1999, 5, 537–545.
+
HRMS (CI+) C21H21CrNO4 ([M]+) requires 403.0876; found 403.0880.
[(3S,4S)-N(2),3-dimethyl-4-phenyl-7-methoxy-1,2,3,4-tetrahydroisoquino-
line]tricarbonylchromium(0) (205 mg, 0.51 mmol) was decomplexed ac-
cording to general procedure 5 to give, after purification by means of re-
[12] S. G. Davies, Organotransition Metal Chemistry: Applications to Or-
ganic Synthesis, Pergamon Press, Oxford, 1982; J. Blagg, S. G.
Davies, N. J. Holman, C. A. Laughton, B. E. Mobbs, J. Chem. Soc.
Perkin Trans. 1 1986, 1581; J. Blagg, S. G. Davies, C. L. Goodfellow,
K. H. Sutton, J. Chem. Soc. Perkin Trans. 1 1987, 1805; S. J. Coote,
S. G. Davies, D. Middlemiss, A. Naylor, Tetrahedron: Asymmetry
1990, 1, 33; S. J. Coote, S. G. Davies, D. Middlemiss, A. Naylor, Tet-
rahedron Lett. 1989, 30, 3581; S. G. Davies, R. F. Newton, J. M. J.
Williams, Tetrahedron Lett. 1989, 30, 2867; S. G. Davies, T. J. Dono-
hoe, J. M. J. Williams, Pure Appl. Chem. 1992, 64, 379; S. G. Davies,
T. J. Donohoe, M. A. Lister, Tetrahedron: Asymmetry 1991, 2, 1085;
S. G. Davies, T. J. Donohoe, Selective Reactions of Metal-Activated
Molecules (Eds.: H. Werner, A. G. Griesbeck, W. Adam, G. Bring-
mann, W. Kiefer), Vieweg, Braunschweig, 1992, 9; S. G. Davies, T. J.
Donohoe, M. A. Lister, Tetrahedron: Asymmetry 1991, 2, 1089.
[13] S. J. Coote, S. G. Davies, D. Middlemiss, A. Naylor, J. Chem. Soc.
Perkin Trans. 1 1989, 2223.
crystallization (Et2O/hexane), 46 as
a white powder (112 mg, 82%,
>99:1 d.r.); m.p.: 1228C (Et2O/hexane); [a]2D0 =+144 (c=0.1 in CHCl3).
[(3S,4S)-N(2),3-Dimethyl-4-phenyl-7-methoxy-1,2,3,4-tetrahydroisoquino-
line]tricarbonylchromium(0) (30 mg, 0.08 mmol) was decomplexed ac-
cording to general procedure 5 to give 71 as a white powder (20 mg,
quant,>99:1 d.r.). Purification of an aliquot by means of recrystallization
(Et2O/hexane) afforded an analytically pure sample of 71; m.p.: 151–
1528C (Et2O/hexane); [a]2D0 =+232 (c=0.1 in CHCl3); 1H NMR
(400 MHz, CDCl3): d=0.88 (3H, d, J=6.6 Hz, C(3)CH3), 2.29 (3H, s,
NCH3), 2.62 (1H, dq, J=6.6, 3.8 Hz, C(3)H), 3.55 (3H, s, OCH3), 3.98
(1H, d, J=3.8 Hz, C(4)H), 3.45 (1H, d, J=15.5 Hz, C(1)HA), 4.09 (1H,
d, J=15.5 Hz, C(1)HB), 6.57–7.28 ppm (8H, m, Ph, Ar); MS (CI): m/z:
267 ([M]+, 100%); elemental analysis: calcd (%) for C18H21NO: C 80.9,
H 7.9, N 5.2; found: C 80.8, H 8.1, N 5.0.
[14] S. J. Coote, S. G. Davies, Chem. Commun. 1988, 648.
[15] It has been reported that N-(3,4-dimethoxybenzyl)-N-methyl-1-
phenyl-2-phenyl-ethanolamine undergoes an acid-mediated cycliza-
tion reaction to give trans-N-methyl-3-phenyl-4-phenyl-6,7-dime-
thoxy-1,2,3,4-tetrahydroisoquinoline, see: H. Hara, R. Shirai, O.
Hoshino, B. Umezawa, Heterocycles 1983, 20, 1945.
[16] For a recent Lewis acid-catalysed example of the synthesis of tetra-
hydroisoquinolines from the corresponding g-amino alcohols, see:
M. Dorbec, J.-C. Florent, C. Monneret, M.-N. Rager, C. Fosse, E.
Bertounesque, Eur. J. Org. Chem. 2008, 1723.
Acknowledgements
The authors would like to thank Glaxo Group (WARE) for a studentship
(S.J.C.) and Dr David J. Watkin and the Oxford Chemical Crystallogra-
phy Service for the use of their X-ray diffractometers.
[1] For brevity 1,2,3,4-tetrahydroisoquinolines will be referred to
throughout this manuscript as tetrahydroisoquinolines.
[2] British National Formulary, No. 4, British Medical Association,
London, 1982.
[17] T. J. Schwan, G. S. Lougheed, S. E. Burrows, J. Heterocycl. Chem.
1974, 11, 807.
[18] L. M. Jackman, V. R. Haddon, J. Am. Chem. Soc. 1974, 96, 5130; M.
Gates, D. L. Frank, W. C. von Felten, J. Am. Chem. Soc. 1974, 96,
5138; T. Ando, J. Yamawaki, Y. Saito, Y. Takai, K. Yamataka, Bull.
Chem. Soc. Jpn. 1980, 53, 2348; A. Pelter, R. S. Ward, R. R. Rao,
Tetrahedron 1985, 41, 2933.
[3] P. A. Dandridge, C. Kaiser, M. Brenner, D. Gaitanopoulos, L. D.
Davis, R. L. Webb, J. J. Foley, H. M. Sarau, J. Med. Chem. 1984, 27,
28; R. Kunstmann, H. Gerhards, H. Kruse, M. Leven, E. F. Paulus,
U. Schacht, K. Schmitt, P. U. Witte, J. Med. Chem. 1987, 30, 798.
[4] B. E. Maryanoff, D. F. McComsey, M. J. Costanzo, P. E. Setler, J. F.
Gardocki, R. P. Shank, C. R. Schneider, J. Med. Chem. 1984, 27,
943; R. C. Griffith, R. J. Gentile, R. C. Robichaud, J. Frankenheim,
J. Med. Chem. 1984, 27, 995; B. E. Maryanoff, D. F. McComsey, J. F.
Gardocki, R. P. Shank, M. J. Costanzo, S. O. Nortey, C. R. Schneider,
P. E. Setler, J. Med. Chem. 1987, 30, 1433; J. N. Jacob, D. E. Nichols,
J. D. Kohli, D. Glock, J. Med. Chem. 1981, 24, 1013; E. Zara-Kac-
zian, G. G. Deak, A. Seregi, M. Doda, J. Med. Chem. 1986, 29, 1189;
R. M. Riggs, D. E. Nichols, M. M. Foreman, L. L. Truex, D. Glock,
J. D. Kohli, J. Med. Chem. 1987, 30, 1454; B. E. Maryanoff, D. F.
McComsey, M. S. Mutter, K. L. Sorgi, C. A. Maryanoff, Tetrahedron
Lett. 1988, 29, 5073; G. Bobowski, J. M. Gottlieb, B. West, J. Hetero-
cycl. Chem. 1980, 17, 1563; G. Bobowski , J. M. Gottlieb, J. Hetero-
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[19] 1H NMR 3J coupling constants are diagnostic in these systems, see:
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