Organocatalytic asymmetric destruction of 1-benzylated Reissert compounds catalysed by quaternary cinchona alkaloids

Article abstract of DOI:10.1039/b710494d

The enantiomeric enrichment of racemic 1-benzylated Reissert compounds under organocatalytic biphasic conditions is presented. The enrichment is the consequence of an asymmetric destruction of the racemic compounds resulting in the formation of the corres

Full text of DOI:10.1039/b710494d

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PAPER
www.rsc.org/obc | Organic & Biomolecular Chemistry
Organocatalytic asymmetric destruction of 1-benzylated Reissert compounds
catalysed by quaternary cinchona alkaloids†
Kim Frisch and Karl Anker Jørgensen*
Received 10th July 2007, Accepted 12th July 2007
First published as an Advance Article on the web 6th August 2007
DOI: 10.1039/b710494d
The enantiomeric enrichment of racemic 1-benzylated Reissert compounds under organocatalytic
biphasic conditions is presented. The enrichment is the consequence of an asymmetric destruction of
the racemic compounds resulting in the formation of the corresponding 1-benzylated isoquinolines.
The highest selectivity has been achieved using quaternary cinchona alkaloids as phase-transfer
catalysts. The resolution of a number of racemic 1-benzylated Reissert compounds reveals a significant
substrate dependence and a proposal for the mechanism of the reaction is presented.
to high yield (68–98%) and low to moderate enantiomeric excess
(20–65%) using N-benzylcinchoninium bromide as phase-transfer
Introduction
Heterocycles derived from isoquinoline have a special focus in
catalyst.
organic chemistry;1 this being due to their abundance in nature2
We wondered whether higher enantioselectivities could be
and the fact that many display biological activity.3 Often these
compounds are optically active and contain a chiral center in the
C-1 position of the isoquinoline ring system.
obtained with compounds 1 derived from acid chlorides (i.e. R1 =
alkyl, Ar) rather than chloroformates due to proximity effects
of the R1 substituent. However, with benzyl bromide or iodide
as alkylating agent, high yields (>70%), but low enantiomeric
excesses (<30% ee) were obtained for all chiral phase-transfer
catalysts and reaction conditions tested (Scheme 1). The low
selectivities proved to be the result of racemic background
reactions.
Reissert compounds, derived from isoquinolines (i.e. 2-acyl-
1,2-dihydroisoquinoline-1-carbonitriles 1), are classical examples
of synthetic isoquinoline derivatives bearing a C-1 chiral carbon
atom. Since the first synthesis of these compounds in 1905 (by the
reaction now known as the Reissert reaction),4 a number of studies
on the addition of electrophiles to the C-1 position have appeared
in the literature.5
In particular, racemic alkylations of Reissert compounds,
resulting in products containing a quaternary stereocenter, have
appeared frequently.6 However, it was not until recently that
an enantioselective alkylation was reported by Rozwadowska
et al.7,8 Under liquid–liquid phase-transfer conditions (e.g. 50% aq.
NaOH–toluene), they reported on the enantioselective alkylation
of racemic Reissert compounds, derived from various chlorofor-
mates (i.e. R1 = O-alkyl, OBn, OPh in structure 1). In the presence
of benzyl bromide, the compounds were benzylated with moderate
Benzyl chloride was tested as well, but with this alkylating
agent, only irreproducible results were obtained. To explain this,
we examined the reaction more closely and found that the varying
results were caused by hydrolysis of the formed products 2.9 This
reaction, leading to formation of the corresponding 1-substituted
isoquinoline 3, is well-known.10 However, our investigations
revealed that the enantiomers of 2 were hydrolysed at different
rates due to the presence of the chiral phase-transfer catalyst; thus
giving rise to an enantiomeric enrichment of 2.
Intrigued by this observation, we set out to investigate, in
detail, this novel asymmetric destruction, or in other words kinetic
resolution, of 1-benzylated Reissert compounds. In this paper, the
results of our investigations are presented.
Danish National Research Foundation: Center for Catalysis, Department
of Chemistry, Aarhus University, DK-8000, Aarhus C, Denmark. E-mail:
kaj@chem.au.dk; Fax: +45 86196199; Tel: +45 89423910
Results and discussion
† Electronic supplementary information (ESI) available: Derivation of
eqn (2) and the equation (for er vs. time) used in Fig. 1a, determination of
conversion and s-values by HPLC and copies of 1H and 13C NMR spectra
for compounds 2a–2k and 3a–3f. See DOI: 10.1039/b710494d
We initiated our study of the asymmetric destruction of
1-benzylated Reissert compounds by examining the hydrolysis of
Scheme 1 Asymmetric alkylation of Reissert compounds derived from acid chlorides (R1 = alkyl, Ar) under alkaline biphasic conditions.
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Table 1 Screening of phase-transfer catalysts for the asymmetric destruction of 2aa
Entry
Catalyst
R1
R2
X
Time/h
Conversionb (%)
eec(%)
sd
1
2
3
4
5
6
7
8
9
10
11
12
13
None
4
—
—
—
—
—
Bn
Bn
—
—
—
—
—
H
Allyl
H
H
H
H
—
—
—
—
—
—
—
Cl
Br
Br
Br
Br
Cl
—
—
70
0.2
4
1.5
3.5
4
42
44
4.5
5
0
79
47
53
70
62
27
27
51
52
63
34
27
0
—
10
(−) 4
1.1
1.1
2.0
1.9
4.7
1.5
1.4
5.0
6.3
6.2
5.7
3.1
5
6a
6b
6c
6d
6e
6f
(−) 25
(−) 37
(+) 68
(+) 6
Anthracenylmethyl
4-OMe-Bn
4-CF3-Bn
4-NO2-Bn
—
(+) 6
(+) 51
(+) 60
(+) 79
(+) 32
(+) 17
6g
6h
6i
9
5
4
6j
—
a Reactions were performed with 0.10 mmol 2a and with 10 mol% phase-transfer catalyst in a mixture of 10 N aq. NaOH and CH2Cl2 (1 : 1) at rt.
b Determined by HPLC. c Enantiomeric excess of recovered 2a determined by chiral HPLC. The parentheses enclose the sign of the optical rotation.
d Calculated using eqn (2).
racemic 2a in the presence of a number of chiral phase-transfer
catalysts (eqn (1) and Table 1).
have been obtained using eqn (2) for different sets of conversion
and enantiomeric excess, which indicate that the equation is
valid throughout the reaction. This test has been carried out
for a number of catalysts and in Fig. 1b, three examples are
presented. The figure illustrates the good correlation between the
experimental data (dots) and theoretical data (curves) obtained
from eqn (2). In fact, the s-values calculated from each of the
experimental data points varied with no more than 0.2 within
the time-interval studied.
(1)
app
fast
app
slow
The selectivities of the catalysts are reported as the stereo-
k
k
ln((1 − conv)(1 − ee))
ln((1 − conv)(1 + ee))
app
selectivity factor s = kafapspt/k , where kapp and kaslpopw are the apparent
s =
=
(2)
slow
fast
rate constants for the fastest and the slowest reacting enantiomer
app
slow
of 2a, respectively. The ratio kafapspt/k
is determined by the
Some representative results from the screening of catalysts are
reported in Table 1. The screening revealed that derivatives of
binaphthyl 4 and ephedrine 5 were less selective than catalysts
derived from cinchona alkaloids 6a–j (entries 2 and 3 vs. 4–
6).12 For the latter class, catalysts derived from quinine and
cinchonidine were observed to be less selective than catalysts
derived from cinchonine (entries 4 and 5 vs. 6). For the cinchonine
derivatives, the hydroxy-group proved to be essential. For example,
expression given in eqn (2), where “conv” is the conversion of
the hydrolysis and ee is the enantiomeric excess of the enriched
Reissert compound.
It should be noted that, although the mechanism in this case
is considered to be more complex (see mechanistic discussion
below), the expression appears similar to the one derived for kinetic
resolutions based on simple first order kinetics.11 Similar s-values
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Fig. 1 (a) Plots of enantiomeric ratio (er) vs. time and (b) enantiomeric excess (ee) vs. conversion for the asymmetric destruction of 2a in the presence of
phase-transfer catalyst 6b, 6c or 6g. Reactions were performed with 0.10 mmol 2a and with 10 mol% catalyst in a mixture of 10 N aq. NaOH and CH2Cl2
(1 : 1) at rt. The dots represent experimental data, while the full lines are obtained from calculations. The er, ee and conversion were measured by chiral
HPLC.
significantly higher selectivity was observed for catalyst 6c, having
an unsubstituted oxygen atom, compared to the O-allylated 6d
(entry 6 vs. 7). For the substituent on the quaternary nitrogen
atom, higher selectivity was observed for cinchoninium catalysts
quaternised by benzyl rather than anthracenylmethyl (entry 6 vs.
8). It was also observed that monomeric catalysts were more
selective than dimeric ones (entry 6 vs. 13). An increase in the
electron density of the N-benzyl substituent was not observed to
have any effect on the selectivity (entry 6 vs. 9). On the other hand,
a decrease in the electron density resulted in a higher selectivity
(entry 6 vs. 10 and 11). This effect was observed to reach a
maximum with a CF3-group in the para-position of the aromatic
N-substituent (entry 10 vs. 11).
Thus, the most selective catalyst for the asymmetric hydrolysis
of 2a proved to be the commercially available N-(4-trifluoro-
methylbenzyl)-cinchoninium bromide 6g, providing a selectivity
of s = 6.3. This catalyst was selected for further investigations.
In the presence of catalyst 6g, we monitored the asymmetric
hydrolysis of racemic 2a over time at room temperature (Fig. 1).
The results are plotted as the enantiomeric ratio (er) of recovered
2a vs. time in Fig. 1a, and as the enantiomeric excess (ee) vs.
conversion in Fig. 1b. The plots illustrate, for example, that
2a is enriched to 11.5 er (i.e. 84% ee) within 9 h under the
applied conditions (Fig. 1a). At this point, the reaction has
proceeded with ca. 66% conversion and thus ca. 34% enriched 2a
remains (Fig. 1b). As for any non-dynamic kinetic resolution, the
maximum possible yield of enantiopure compound is 50% when
starting from a racemate. For comparison, the results obtained for
the less selective catalysts 6b and 6c are included.
In line with Fig. 1b, the plots in Fig. 1a illustrate a good
correlation (R2 ≥ 0.986) between the experimental data and the
expected theoretical change in enantiomeric ratio.13
A screening of reaction conditions and additives was carried
out as well and a number of results are presented in Table 2. For
the solvent screening, significantly lower reactivity and selectivity
were observed for solvents such as Et2O and toluene compared
to ClCH2CH2Cl and CH2Cl2 (entries 1 and 2 vs. 3 and 4). This
observation was attributed a lower solubility of the phase-transfer
catalyst in the former solvents. A lowering of the concentration of
the applied aq. NaOH from 10 to 3 N was not observed to have
any effect on the selectivity. Only the rate of the hydrolysis was
affected (entry 4 vs. 5). With a solid-liquid phase-transfer system
(KOH–organic solvent), the reaction was significantly slower and
unidentified by-products were formed. Addition of a surfactant
such as Triton X-405 for micelle formation proved to have a
negative effect on the selectivity (entry 4 vs. 6). On the other hand,
a decrease in the temperature was observed to have a significant
effect. Thus, lowering the temperature from room temperature to
Table 2 Screening of reaction conditions and additives for the asymmetric destruction of 2a catalysed by 6ga
Entry
Organic solvent
Temp./◦C
Time/h
Conversionb(%)
eec(%)
sd
1.8
3.2
6.1
6.3
6.2
4.5
10.3
10.1
1
2
3
Et2O
rt
rt
rt
rt
5
5
5
5
5
4
26
118
13
23
47
52
21
52
43
33
(+) 4
(+) 14
(+) 51
(+) 60
(+) 18
(+) 51
(+) 54
(+) 37
Toluene
ClCH2CH2Cl
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
4
5e
6f
7
rt
rt
5
8
−20
a Reactions were performed with 0.10 mmol 2a and with 10 mol% phase-transfer catalyst 6g in a mixture of 10 N aq. NaOH (unless otherwise stated)
and an organic solvent (1 : 1). b Determined by HPLC. c Enantiomeric excess of recovered 2a determined by chiral HPLC. The parentheses enclose the
sign of the optical rotation. d Calculated using eqn (2). e 3 N aq. NaOH was applied instead of 10 N. f The surfactant Triton X-405 (0.3 eq.) was used as
additive.
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Table 3 Asymmetric destruction of 1-benzylated Reissert compounds in the presence of phase-transfer catalyst 6ga
Entry
Substrate
Product
R1
R2
R3
Time/h
Conversionb(%)
eec(%)
sd
1
2e
3
4
5
6
7
8
9
2a
2a
2b
2c
2d
2e
2f
2g
2h
2i
3a
3a
3a
3a
3a
3a
3a
3b
3c
3d
3e
3f
Phenyl
Phenyl
4-OMe-phenyl
3,5-DiOMe-phenyl
4-Br-phenyl
Me
iPr
Phenyl
Phenyl
Phenyl
H
H
H
H
H
H
H
4-OMe
4-CN
H
H
H
H
H
H
H
H
H
H
H
26
26
24
72
5
24
145
24
18
24
1
43 (56)
52 (n.d.)
33 (67)
33 (64)
40 (49)
44 (50)
n.d.f(46)
46 (53)
80 (20)
51 (49)
44 (48)
34 (66)
(+) 54
(+) 67
(+) 31
(+) 35
(+) 48
(+) 46
(+) 6
9.9
8.8
6.0
7.9
9.7
5.8
—
7.5
4.9
9.7
1.2
3.8
(+) 53
(+) 95
(+) 69
(+) 8
H
10
11
12
5-OMe
5-Br
4-Br
2j
2k
Phenyl
Phenyl
0.2
(−) 25
a Reactions were performed with 0.10 mmol 2a–k and with 10 mol% phase-transfer catalyst 6g in a mixture of 10 N aq. NaOH and CH2Cl2 (1 : 1) at
5 ◦C. All data is for a particular run except the stereoselectivity factor s which is the average of two runs ( 0.4). b Determined by HPLC. The number in
parentheses is the amount of non-racemic 2a–k recovered by chromatography. c Enantiomeric excess of recovered 2a–k determined by chiral HPLC. The
parentheses enclose the sign of the optical rotation. d Calculated using eqn (2). e The reaction was performed with 0.40 mmol 2a. The concentrations were
maintained. f Conversion could not be determined due to the formation of several (unidentifiable) by-products.
5 ◦C led to an increase in selectivity from s = 6.3 to s = 10.3 (entry 4
stereoselectivity factor could not be determined. However, from
the enantiomeric excess and the amount of recovered substrate,
the selectivity was expected to be low.
◦
vs. 7). An additional decrease in the temperature to −20 C did
not improve the selectivity further (entry 7 vs. 8).
With the reaction conditions providing the highest selectivity
for compound 2a, a number of 1-benzylated Reissert compounds
were investigated (eqn (3)). The results are presented in Table 3.
All reactions were carried out on a 0.10 mmol scale. For reactions
of larger scale (e.g. 0.40 mmol with maintained concentrations),
lower selectivity was observed (entry 1 vs. 2). In most cases, all
of the non-reacted enantiomerically enriched Reissert compound
could be recovered after quenching (see column 8 in the table).
With the exception of compound 2k, all substrates investigated
were enriched in their (+)-enantiomer (see column 9 in the table)
in the presence of catalyst 6g.
Next, the substitution on the 1-benzyl substituent (R2) was
varied. Substrate 2g, having the electron-donating methoxy-group
in the para-position of the benzyl-substitutent, was resolved with
an average s-value of 7.5 (entry 8), while the corresponding
substrate substituted with the electron-withdrawing cyano-group
(2h) was resolved with an average s-value of 4.9 (entry 9).
Finally, the substitution on the isoquinoline moiety (R3) was
varied. In this case, it is interesting to note the large difference
in reaction rate observed for the similar compounds 2a, 2i and
2j. Although the R3 substituent (i.e. H, OMe, Br) is in a position
remote to the carbonyl group, compound 2j reacts significantly
faster than 2a and 2i (compare entries 1, 10 and 11). Moreover,
lower selectivity is observed for the electron-poor substrates 2j
and 2k compared to the less reactive 2a and the electron-rich
2i (compare entries 1 and 10–12). A similar trend is observed
for compounds 2g and 2h (entries 8 and 9). However, an overall
simple reactivity–selectivity relationship does not seem to exist for
the reaction (compare e.g. entries 1, 5 and 11).
(3)
Since the lowest selectivities were obtained for the electron-
deficient substrates using the electron-poor catalyst 6g (with the
exception of substrate 2d), a number of alternative catalysts were
tested for these substrates (Table 4). For example, the electron-rich
catalyst 6f was applied for the hydrolysis of substrates 2h, 2j and
2k (entries 2, 4 and 6). All reacted faster than in the presence of
6g, but with similar or lower selectivity. Interestingly, compound
2j was enriched in opposite enantiomers using catalyst 6f and 6g
(compare Table 3; entry 11 and Table 4; entry 4). Since the two
catalysts are both derived from cinchonine, differing only in the
substitution of the N-benzyl group, this observation indicates a
sensitive interaction between substrate and catalyst.
A further testing of catalysts also revealed that a significant
increase in selectivity was obtained, when substrates 2j and 2k were
resolved in the presence of the cinchonidine derived 6b (Table 4;
entries 3 and 5). In the presence of this catalyst, 2j and 2k reacted
fast and were resolved with stereoselectivity factors of 3.5 and 5.7,
respectively. On the other hand, compound 2h also reacted fast in
the presence of 6b, but with a low selectivity of 1.4 (entry 1).
The first variation in substitution of the substrates was for the N-
protecting group (R1). Compared to substrate 2a, lower selectivity
was observed for substrates having electron-rich benzoyl-groups,
such as 2b and 2c (entries 3 and 4 vs. 1). On the other hand,
the electron-poor 2d was resolved with selectivity similar to that
of 2a (entry 5 vs. 1). This compound reacted significantly faster
than compounds 2a–c most likely due to the electron-withdrawing
bromine increasing the electrophilicity of the carbonyl-group.
Substrates with N-alkylcarbonyl groups were also tested. The N-
acetyl compound 2e displayed reactivity similar to that of 2a, but
was resolved with lower selectivity (entry 6 vs. 1). Compound 2f,
having the more bulky isopropyl group adjacent to the carbonyl
group, was observed to hydrolyse significantly slower than the
methyl analogue 2e (entry 7 vs. 6). Moreover, the reaction of this
substrate proceeded with formation of several by-products and
because not all of these products could be identified, a value for the
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Table 4 Asymmetric destruction of compounds 2h, 2j, 2k in the presence of phase-transfer catalyst 6f or 6ba
Entry
Substrate
Catalyst
Time/min
Conversionb(%)
eec(%)
sd
1
2
3
4
5
6
2h
2h
2j
6b
6f
6b
6f
6b
6f
60
240
30
60
2
42
68
70
81
60
40
(−) 9
(+) 59
(+) 69
(−) 21
(+) 71
(−) 31
1.4
3.0
3.5
1.3
5.7
3.7
2j
2k
2k
2
a Reactions were performed with 0.10 mmol substrate and with 10 mol% catalyst in a mixture of 10 N aq. NaOH and CH2Cl2 (1 : 1) at 5 ◦C. b Determined
by HPLC. c Enantiomeric excess of recovered 2 determined by chiral HPLC. The parentheses enclose the sign of the optical rotation. d Calculated using
eqn (2).
Our mechanistic proposal for this novel asymmetric destruction
of 1-benzylated Reissert compounds is outlined in Scheme 2 and
Scheme 3. The proposal is illustrated for compound 2a.
matching of the two chiral ions of 7 to be influenced by hydrogen-
bonding and aromatic interactions.
Kinetic considerations reveal that the selectivity s is dictated by
app
slow
Initially, the racemic Reissert compounds ( )-2a and the chiral
phase-transfer catalyst (*R4NZ, Z = halide) are present in
the organic phase, while hydroxide ions reside in the aqueous
phase (Scheme 2). At the interface between the organic and
aqueous phase, an ion-exchange occurs to give a sodium salt
(NaZ) and a chiral ion-pair consisting of the catalyst cation
and hydroxide (*R4NOH). While NaZ diffuses to the aqueous
phase, the lipophilic *R4NOH diffuses to the organic phase. In
this phase, *R4NOH reacts with the carbonyl group of ( )-2a to
give intermediate 7, which subsequently loses benzoate yielding a-
amino nitrile 8 and ensures regeneration of the catalyst (Scheme 3).
The reaction step 2a → 7 is expected to be fast and reversible,
and the step 7 → 8 irreversible and rate determining. Thus,
the overall the reaction is expected to follow Michaelis–Menten
kinetics.11a
both the stability and the reactivity of 7. That is, the ratio kafapspt/k
is expressed by the equilibrium constants for the formation
and the rate constants for the decomposition of each of the
diastereomers of 7.14 The involvement of both factors may explain
the significant substrate dependence observed. Also, it might
explain the relatively low selectivities obtained (e.g. one of the
diastereomers, derived from (+)-2a, may be just as stable/reactive
as one derived from (−)-2a).
The further reaction of 8 is expected to be a fast retro-Strecker
reaction (i.e. loss of HCN and formation of the imine 3a).15 In
fact, a-amino nitriles are known to undergo retro-Strecker reaction
under both acidic and basic conditions.16 However, heating is often
required to afford the elimination of HCN with high conversion.
We believe that the aromatisation, associated with the formation
of 3a, provides the driving force for the loss of HCN from 8 at the
low temperature applied.
The reaction between the enantiopure *R4NOH and 2a, result-
ing in four possible diastereomers of 7, gives rise to a complex
match/mismatch situation. Besides configurations, we expect the
It has also been reported that N-formylation is an effective
way to protect a-amino nitriles otherwise prone to retro-Strecker
Scheme 2 Mechanistic proposal for the asymmetric destruction of 1-benzylated Reissert compounds exemplified by substrate 2a (Z = halide, cyanide
or benzoate).
Scheme 3 Proposed reaction between 2a and *R4NOH.
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reaction.16a,16b,16f Again, the formation of the aromatic 3a may
explain why 2a undergoes an overall retro-Strecker reaction despite
the presence of the N-benzoyl group.
Asymmetric destruction of 2-benzoyl-1-benzyl-1,2-dihydroiso-
quinoline-1-carbonitrile (2a) (typical procedure). Racemic 2a
(35.0 mg, 0.10 mmol) was dissolved in CH2Cl2 (0.5 mL) in
a small glass vial with stirring and N-(4-(trifluoromethyl)-
benzyl)cinchoninium bromide 6g (5.3 mg, 0.01 mmol) was added.
The vial was closed and the mixture was cooled to 5 ◦C before
cold (5 ◦C) 10 N aqueous NaOH (0.5 mL) was added. The
heterogeneous mixture was stirred vigorously at 5 ◦C for 26 h. The
two layers were separated using more CH2Cl2 and H2O (ca. 1 mL
each) and the aqueous layer was extracted three times with CH2Cl2
(ca. 1 mL). The combined organic layers were eluted through a
short pad of SiO2 using Et2O as the eluent, then washed with
H2O and finally with brine. After drying (MgSO4) and filtering the
organic layers, a small sample was collected for HPLC analysis
(43% conv., 54% ee, s = 10.3). The solvents were then evaporated to
obtain an oily mixture of 2a and 3a. The mixture was separated by
FC on SiO2 (eluent: gradual polarity change from hexane to 80%
Et2O in hexane) to give the enantiomerically enriched 2-benzoyl-1-
benzyl-1,2-dihydroisoquinoline-1-carbonitrile 2a as an oil, which
turned into a white solid when dried under vacuum overnight
(19.5 mg, 56%). 1H NMR (CDCl3) d 7.64 (d, J = 7.4 Hz, 2H), 7.55
(t, J = 7.2 Hz, 1H), 7.44–7.51 (m, 2H), 7.31 (d, J = 7.2 Hz, 1H),
7.11–7.25 (m, 5H), 7.02 (d, J = 7.5 Hz, 1H), 6.83 (d, J = 7.4 Hz,
2H), 6.36 (d, J = 7.9 Hz, 1H), 5.54 (d, J = 8.0 Hz, 1H), 3.73 (d, J =
13.0 Hz, 1H), 3.53 (d, J = 12.9 Hz, 1H). 13C NMR (CDCl3) d 169.4,
133.1, 133.0, 131.9, 130.9, 129.4, 129.3, 129.0, 128.6, 127.9, 127.7,
127.6, 127.4, 127.3, 126.4, 124.7, 117.6, 106.6, 61.3, 43.3. HRMS:
C24H18N2O [M + Na]+ calcd.: 373.1311, found: 373.1316. [a]2D3
+100.3 (13 mg mL−1 CHCl3, 57% ee). HPLC: Daicel Chiralpak
Conclusions
In conclusion, we have reported on the asymmetric destruc-
tion of 1-benzylated Reissert compounds under phase-transfer
conditions. This novel reaction was studied in detail in the
presence of various phase-transfer catalysts and under different
reaction conditions. Catalysts derived from cinchona alkaloids
resulted in the highest selectivity. The most selective proved
to be the commercially available N-(4-trifluoromethyl-benzyl)-
cinchoninium bromide 6g, which provided a stereoselectivity
factor s of 10 for model substrate 2a. In general, however,
the reaction was observed to be very substrate dependent and
a mechanistic proposal suggesting a complex match/mismatch
between substrate and catalyst has been presented.
Finally, we believe that further development of the reaction may
result in an approach, alternative to the existing,7,8 for the synthesis
of optically active 1-alkylated Reissert compounds. Additionally,
this work adds to a short list of reported kinetic resolutions
catalysed by quaternary cinchona alkaloids.17
Experimental
General methods
AD column [hexane–iPrOH (95 : 5)]; flow rate 1.0 mL min−1 (s3a
12.1 min; s2a,minor = 25.4 min; s 2a,major = 27.5 min).
=
NMR spectra were acquired on a Varian AS 400 spectrometer,
running at 400 and 100 MHz for 1H and 13C, respectively.
Chemical shifts (d) are reported in ppm relative to CDCl3 (d =
7.26) or acetone-d6 (d = 2.05) for 1H NMR and relative to
the central resonance of CDCl3 (d = 77.0) or acetone-d6 (d =
29.84) for 13C NMR. 13C NMR spectra were acquired on a
broad band decoupled mode. Mass spectra were recorded on a
micromass LCT spectrometer using electrospray (ES+) ionization
techniques. Optical rotations were measured on a Perkin-Elmer
241 polarimeter. For compounds 2a–k, 3c and 3e, flash column
chromatography (FC) was carried out using a Flashmaster II
from Jones Chromatography. The enantiomeric excess (ee) of
the Reissert compounds and the conversions of the asymmetric
destructions were determined by chiral stationary phase HPLC
(Daicel Chiralpak AD/AS or Daicel Chiralcel OD columns).
1-Benzyl-2-(4-methoxybenzoyl)-1,2-dihydroisoquinoline-1-carbo-
nitrile (2b). The title compound was asymmetrically destroyed
according to the procedure described for compound 2a. Reaction
time: 24 h. HPLC-analysis: 33% conv., 31% ee, s = 5.6. FC
conditions: SiO2, eluent: gradual polarity change from CH2Cl2
to 4% Et2O in CH2Cl2. Recovered enantiomerically enriched 2b:
1
67%. Appearance: white solid. H NMR (CDCl3) d 7.64 (d, J =
8.6 Hz, 2H), 7.30 (m, 1H), 7.21 (t, J = 7.3 Hz, 1H), 7.09–7.17 (m,
4H), 7.03 (d, J = 7.2 Hz, 1H), 6.95 (d, J = 8.9 Hz, 2H), 6.82 (d,
J = 7.5 Hz, 2H), 6.43 (d, J = 7.9 Hz, 1H), 5.59 (d, J = 8.0 Hz,
1H), 3.88 (s, 3H), 3.67 (d, J = 12.8 Hz, 1H), 3.55 (d, J = 12.9 Hz,
1H). 13C NMR (CDCl3) d 169.0, 162.6, 133.1, 131.8, 130.9, 129.3,
129.2, 127.8, 127.7, 127.4, 127.1, 126.9, 125.1, 124.6, 117.6, 113.9,
106.3, 61.6, 55.5, 42.9. HRMS: C25H20N2O2 [M + Na]+ calcd.:
403.1417, found: 403.1414. [a]2D3 +62.0 (10 mg mL−1 CHCl3,
31% ee). HPLC: Daicel Chiralcel OD column [hexane–iPrOH
(90 : 10)]; flow rate 1.0 mL min−1 (s3a = 9.3 min; s2b,minor = 14.2 min;
s2b,major = 19.6 min).
Materials
Analytical grade solvents were used as received. For FC, silica gel
from Iatron Laboratories Inc. (Iatrobeads 6RS-8060) or silica gel
60, 230–400 mesh was used. The racemic 1-benzylated Reissert
compounds 2a–k were synthesized using literature procedures (all
were purified by recrystallization from EtOH; except compounds
2d and 2i, which were purified by FC).18 5-Methoxyisoquinoline
(used for the preparation of substrate 2i) was prepared (NaH
then MeI in DMF at 0–5 ◦C) from commercially available
5-hydroxyisoquinoline.19 Phase-transfer catalysts 6f,20 6h,20 6i21
and 6j22 were prepared from commercially available cinchonine
according to literature procedures. All other compounds were
obtained from commercial sources and used as received.
1-Benzyl-2-(3,5-dimethoxybenzoyl)-1,2-dihydroisoquinoline-1-
carbonitrile (2c). The title compound was asymmetrically de-
stroyed according to the procedure described for compound 2a.
Reaction time: 72 h. HPLC-analysis: 33% conv., 35% ee, s = 7.9.
FC conditions: SiO2, eluent: gradual polarity change from CH2Cl2
to 4% Et2O in CH2Cl2. Recovered enantiomerically enriched 2c:
64%. Appearance: pale yellow solid. 1H NMR (CDCl3) d 7.20 (t,
J = 7.4 Hz, 1H), 7.02–7.15 (m, 5H), 6.92 (d, J = 7.5 Hz, 1H),
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6.73 (d, J = 7.3 Hz, 2H), 6.62 (d, J = 2.2 Hz, 2H), 6.50 (t, J =
2.2 Hz, 1H), 6.27 (d, J = 8.0 Hz, 1H), 5.44 (d, J = 8.0 Hz, 1H),
3.71 (s, 6H), 3.63 (d, J = 13.0 Hz, 1H), 3.42 (d, J = 12.9 Hz,
1H). 13C NMR (CDCl3) d 169.2, 160.8, 135.0, 132.9, 130.9, 129.4,
129.0, 127.9, 127.7, 127.6, 127.5, 127.3, 126.3, 124.8, 117.6, 106.8,
106.5, 104.0, 61.3, 55.60, 55.58, 43.3. HRMS: C26H22N2O3 [M +
Na]+ calcd.: 433.1523, found: 433.1548. [a]2D3 +55.3 (12 mg mL−1
CHCl3, 35% ee). HPLC: Daicel Chiralpak AS column [hexane–
1H), 1.28 (d, J = 6.7 Hz, 3H), 1.25 (d, J = 6.8 Hz, 3H). 13C
NMR (CDCl3) d 175.3, 133.0, 130.7, 129.3, 128.9, 128.4, 127.8,
127.6, 127.44, 127.41, 124.6, 123.5, 118.4, 106.7, 60.3, 44.7, 31.8,
19.3, 18.8. HRMS: C21H20N2O [M + Na]+ calcd.: 339.1468, found:
339.1453. [a]2D3 +9.3 (10 mg mL−1 CHCl3, 6% ee). HPLC: Daicel
Chiralcel OD + Chiralpak AD column [hexane–iPrOH (98 : 2)];
flow rate 1.0 mL min−1 (s2f,major = 38.2 min; s2f,minor = 42.5 min).
iPrOH (90 : 10)]; flow rate 1.0 mL min−1 (s3a = 6.3 min; s2c,minor
=
2-Benzoyl-1-(4-methoxybenzyl)-1,2-dihydroisoquinoline-1-carbo-
nitrile (2g). The title compound was asymmetrically destroyed
according to the procedure described for compound 2a. Reaction
time: 24 h. HPLC-analysis: 46% conv., 53% ee, s = 7.5. FC
conditions: SiO2, eluent: gradual polarity change from CH2Cl2
to 4% Et2O in CH2Cl2. Recovered enantiomerically enriched 2g:
22.3 min; s2c,major = 27.8 min).
1-Benzyl-2-(4-bromobenzoyl)-1,2-dihydroisoquinoline-1-carbo-
nitrile (2d). The title compound was asymmetrically destroyed
according to the procedure described for compound 2a. Reaction
time: 5 h. HPLC-analysis: 40% conv., 48% ee, s = 10.0. FC
conditions: iatrobeads, eluent: gradual polarity change from
hexane to 10% acetone in hexane. Recovered enantiomerically
1
53%. Appearance: pale yellow solid. H NMR (CDCl3) d 7.64
(d, J = 7.5 Hz, 2H), 7.55 (t, J = 7.2 Hz, 1H), 7.47 (m, 2H),
7.30 (dt, J = 1.9, 7.4 Hz, 1H), 7.11–7.23 (m, 2H), 7.02 (d, J =
7.4 Hz, 1H), 6.73 (d, J = 8.6 Hz, 2H), 6.68 (d, J = 8.5 Hz, 2H),
6.36 (d, J = 8.0 Hz, 1H), 5.56 (d, J = 8.0 Hz, 1H), 3.76 (s, 3H),
3.65 (d, J = 13.1 Hz, 1H), 3.48 (d, J = 13.1 Hz, 1H). 13C NMR
(CDCl3) d 169.4, 159.0, 133.2, 131.90, 131.87, 129.4, 129.3, 129.0,
128.6, 127.8, 127.7, 127.3, 126.4, 125.0, 124.7, 117.7, 113.3, 106.6,
61.5, 55.1, 42.4. HRMS: C25H20N2O2 [M + Na]+ calcd.: 403.1417,
found: 403.1400. [a]D23 +70.8 (8 mg mL−1 CHCl3, 53% ee). HPLC:
Daicel Chiralpak AD column [hexane–iPrOH (90 : 10)]; flow
1
enriched 2d: 49%. Appearance: white solid. H NMR (CDCl3) d
7.62 (d, J = 8.6 Hz, 2H), 7.51 (d, J = 8.6 Hz, 2H), 7.31 (ddd, J =
2.1, 6.6, 7.5 Hz, 1H), 7.22 (d, J = 7.4 Hz, 1H), 7.10–7.19 (m, 4H),
7.03 (d, J = 7.3 Hz, 1H), 6.82 (d, J = 6.9 Hz, 2H), 6.3 (d, J = 7.9 Hz,
1H), 5.59 (d, J = 7.9 Hz, 1H), 3.70 (d, J = 12.9 Hz, 1H), 3.52 (d,
J = 12.9 Hz, 1H). 13C NMR (CDCl3) d 168.4, 132.8, 131.9, 130.9,
130.8, 129.5, 128.8, 127.9, 127.70, 127.66, 127.54, 127.51, 126.8,
125.9, 124.9, 117.5, 107.2, 61.4, 43.2. HRMS: C24H17BrN2O [M +
Na+] calcd.: 451.0416, found: 451.0424. [a]2D3 +154.5 (10 mg mL−1
CHCl3, 48% ee). HPLC: Daicel Chiralcel OD column [hexane–
rate 1.0 mL min−1 (s3b = 13.3 min; s2g,minor = 23.5 min; s2g,major
=
27.8 min).
iPrOH (98 : 2)]; flow rate 1.0 mL min−1 (s3a = 16.9 min; s2d,major
=
26.3 min; s2d,minor = 31.1 min).
2-Benzoyl-1-(4-cyanobenzyl)-1,2-dihydroisoquinoline-1-carbo-
nitrile (2h). The title compound was asymmetrically destroyed
according to the procedure described for compound 2a. Reaction
time: 18 h. HPLC-analysis: 80% conv., 95% ee, s = 4.8. FC
conditions: SiO2, eluent: gradual polarity change from CH2Cl2
to 3% Et2O in CH2Cl2. Recovered enantiomerically enriched 2h:
2-Acetyl-1-benzyl-1,2-dihydroisoquinoline-1-carbonitrile (2e).
The title compound was asymmetrically destroyed according to
the procedure described for compound 2a. Reaction time: 24 h.
HPLC-analysis: 44% conv., 46% ee, s = 6.0. FC conditions: SiO2,
eluent: gradual polarity change from hexane to Et2O. Recovered
enantiomerically enriched 2e: 50%. Appearance: pale yellow
1
20%. Appearance: white solid. H NMR (CDCl3) d 7.63 (d, J =
7.1 Hz, 2H), 7.57 (t, J = 7.4 Hz, 1H), 7.42–7.51 (m, 4H), 7.34 (dt,
J = 1.8, 7.1 Hz, 1H), 7.11–7.20 (m, 2H), 7.07 (d, J = 7.5 Hz, 1H),
6.94 (d, J = 8.2 Hz, 2H), 6.39 (d, J = 7.9 Hz, 1H), 5.62 (d, J =
7.9 Hz, 1H), 3.73 (d, J = 12.8 Hz, 1H), 3.59 (d, J = 12.7 Hz,
1H). 13C NMR (CDCl3) d 169.5, 138.5, 132.6, 132.3, 131.61,
131.58, 129.9, 129.4, 128.9, 128.7, 127.5, 127.4, 126.8, 126.4, 125.1,
118.6, 116.9, 111.5, 106.8, 61.0, 42.9. HRMS C25H17N3O2 [M +
Na]+: calcd.: 398.1264, found: 398.1278. [a]2D3 +123.7 (11 mg mL−1
CHCl3, 85% ee). HPLC: Daicel Chiralpak AD column [hexane–
1
solid. H NMR (CDCl3) d 7.32 (d, J = 7.8 Hz, 1H), 7.26 (t,
J = 7.5 Hz, 1H), 7.14–7.23 (m, 2H), 7.10 (t, J = 7.2 Hz, 2H),
6.92 (d, J = 7.5 Hz, 1H), 6.70 (d, J = 7.9 Hz, 2H), 6.33 (d, J =
8.1 Hz, 1H), 5.43 (d, J = 8.1 Hz, 1H), 3.76 (d, J = 13.0 Hz, 1H),
3.26 (d, J = 13.1 Hz. 1H), 2.32 (s, 3H). 13C NMR (acetone-d6) d
169.9, 134.2, 131.5, 130.3, 130.2, 129.1, 128.6, 128.3, 128.1, 127.9,
126.2, 125.6, 119.2, 106.2, 60.7, 45.0, 23.0. HRMS: C19H16N2O
[M + Na]+ calcd.: 311.1155, found: 311.1165. [a]2D3 +43.7 (14 mg
mL−1 CHCl3, 46% ee). HPLC: Daicel Chiralcel OD column
[hexane–iPrOH (90 : 10)]; flow rate 1.0 mL min−1 (s3a = 9.6 min;
s2e,minor = 18.0 min; s2e,major = 22.0 min).
iPrOH (85 : 15)]; flow rate 1.0 mL min−1 (s3c = 16.0 min; s2h,minor
=
27.9 min; s2h,major = 36.9 min).
2-Benzoyl-1-benzyl-5-methoxy-1,2-dihydroisoquinoline-1-carbo-
nitrile (2i). The title compound was asymmetrically destroyed
according to the procedure described for compound 2a. Reaction
time: 24 h. HPLC-analysis: 51% conv., 69% ee, s = 9.5. FC
conditions: SiO2, eluent: gradual polarity change from hexane to
20% acetone in hexane. Recovered enantiomerically enriched 2i:
1-Benzyl-2-isobutyryl-1,2-dihydroisoquinoline-1-carbonitrile (2f).
The title compound was asymmetrically destroyed according
to the procedure described for compound 2a. Reaction time:
145 h. HPLC-analysis: conversion was not determined, 6% ee. FC
conditions: SiO2, eluent: gradual polarity change from hexane to
Et2O. Recovered enantiomerically enriched 2f: 46%. Appearance:
1
49%. Appearance: white solid. H NMR (CDCl3) d 7.63 (d, J =
1
white solid. H NMR (CDCl3) d 7.32 (d, J = 8.3 Hz, 1H), 7.28
7.0 Hz, 2H), 7.54 (t, J = 7.4 Hz, 1H), 7.46 (d, J = 7.7 Hz, 2H),
7.22 (m, 1H), 7.07–7.18 (m, 3H), 6.79–6.91 (m, 4H), 6.34 (d, J =
8.1 Hz, 1H), 5.97 (d, J = 8.1 Hz, 1H), 3.86 (s, 3H), 3.68 (d, J =
12.9 Hz, 1H), 3.53 (d, J = 12.9 Hz, 1H). 13C NMR (CDCl3) d 169.4,
153.3, 133.2, 133.1, 131.9, 130.9, 129.4, 128.8, 128.5, 127.9, 127.8,
(dt, J = 1.2, 7.5 Hz, 1H), 7.15–7.23 (m, 2H), 7.11 (t, J = 7.7 Hz,
2H), 6.95 (dd, J = 1.2, 7.5 Hz, 1H), 6.71 (d, J = 7.1 Hz, 2H),
6.45 (d, J = 8.2 Hz, 1H), 5.47 (d, J = 8.1 Hz, 1H), 3.73 (d, J =
13.0 Hz, 1H), 3.28 (d, J = 13.0 Hz, 1H), 2.92 (septet, J = 6.8 Hz,
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127.4, 125.5, 119.9, 118.4, 117.6, 110.9, 101.2, 61.3, 55.7, 42.8.
HRMS: C25H20N2O2 [M + Na]+ calcd.: 403.1417, found: 403.1425.
[a]2D3 +109.7 (13 mg mL−1 CHCl3, 68% ee). HPLC: Daicel Chiral-
pak AD column [hexane–iPrOH (95 : 5)]; flow rate 1.0 mL min−1
(s3d = 18.9 min; s2i,minor = 40.1 min; s2i,major = 45.2 min).
J = 1.2, 6.9, 8.1 Hz, 1H), 7.49–7.58 (m, 2H), 7.20 (d, J = 8.2 Hz,
2H), 6.80 (d, J = 8.7 Hz, 2H), 4.61 (s, 2H), 3.74 (s, 3H). 13C NMR
(CDCl3) d 160.4, 157.9, 142.0, 136.5, 131.5, 129.8, 129.5, 127.3,
127.13, 127.06, 125.8, 120.0, 113.9, 55.1, 41.2. HRMS: C17H15NO
[M + H]+ calcd.: 250.1226, found: 250.1221.
1-(4-Cyano)benzylisoquinoline (3c). The title compound was
isolated from the asymmetric destruction of Reissert compound
2h. FC conditions: SiO2, eluent: gradual polarity change from
CH2Cl2 to 15% Et2O in CH2Cl2. Appearance: white solid. 1H
NMR (CDCl3) d 8.49 (d, J = 5.7 Hz, 1H), 8.04 (d, J = 8.5 Hz,
1H), 7.83 (d, J = 8.2 Hz, 1H), 7.66 (t, J = 7.1 Hz, 1H), 7.50–
7.59 (m, 4H), 7.37 (d, J = 8.3 Hz, 2H), 4.71 (s, 2H). 13C NMR
(CDCl3) d 158.5, 144.9, 142.1, 136.5, 132.3, 130.1, 129.4, 127.6,
127.0, 125.1, 120.2, 118.9, 110.2, 41.8. HRMS: C17H12N2 [M +
Na]+ calcd.: 267.0893, found: 267.0891.
2-Benzoyl-1-benzyl-5-bromo-1,2-dihydroisoquinoline-1-carbo-
nitrile (2j). The title compound was asymmetrically destroyed
according to the procedure described for compound 2a. Reaction
time: 1 h. HPLC-analysis: 44% conv., 8% ee, s = 1.3. FC
conditions: SiO2, eluent: gradual polarity change from CH2Cl2
to 4% Et2O in CH2Cl2. Recovered enantiomerically enriched 2j:
1
48%. Appearance: white solid. H NMR (CDCl3) d 7.64 (d, J =
7.7 Hz, 2H), 7.44–7.59 (m, 4H), 7.23 (t, J = 5.4 Hz, 1H), 7.15 (t,
J = 7.7 Hz, 2H), 7.06 (d, J = 7.6 Hz, 1H), 6.95 (t, J = 8.0 Hz, 1H),
6.84 (d, J = 7.5 Hz, 2H), 6.46 (d, J = 8.2 Hz, 1H), 5.98 (d, J =
8.2 Hz, 1H), 3.61 (d, J = 12.9 Hz, 1H), 3.54 (d, J = 12.9 Hz, 1H).
13C NMR (CDCl3) d 169.4, 133.5, 132.6, 132.5, 132.3, 130.9, 129.5,
129.4, 128.71, 128.68, 128.1, 128.0, 127.9, 127.7, 127.0, 120.1,
117.1, 105.2, 61.6, 42.7. HRMS: C24H17BrN2O [M + Na]+ calcd.:
451.0398, found: 451.0416. [a]2D3 +9.7 (8 mg mL−1 CHCl3, 8% ee).
HPLC: Daicel Chiralpak AD column [hexane–iPrOH (95 : 5)];
1-Benzyl-5-methoxyisoquinoline (3d). The title compound was
isolated from the asymmetric destruction of Reissert compound
2i. FC conditions: SiO2, eluent: 10% Et2O–DCM. Appearance:
white solid. 1H NMR (CDCl3) d 8.51 (d, J = 5.97 Hz, 1H), 7.96
(d, J = 5.9 Hz, 1H), 7.70 (d, J = 8.5 Hz, 1H), 7.43 (t, J = 8.4 Hz,
1H), 7.21–7.30 (m, 4H), 7.13–7–20 (m, 1H), 6.94 (d, J = 7.8 Hz,
1H), 4.65 (s, 2H), 3.99 (s, 3H). 13C NMR (CDCl3) d 159.4, 154.9,
141.7, 139.5, 129.2, 128.5, 128.4, 127.9, 127.1, 126.1, 117.6, 114.0,
107.1, 55.6, 42.3. HRMS: C17H15NO [M + Na]+ calcd.: 272.1046,
found: 272.1048.
flow rate 1.0 mL min−1 (s3e = 12.2 min; s2j,minor = 21.8 min; s2j,major
=
23.1 min).
2-Benzoyl-1-benzyl-4-bromo-1,2-dihydroisoquinoline-1-carbo-
nitrile (2k). The title compound was asymmetrically destroyed
according to the procedure described for compound 2a. Reaction
time: 10 min. HPLC-analysis: 34% conv., 25% ee, s = 3.7. FC
conditions: SiO2, eluent: gradual polarity change from hexane
to 50% Et2O in hexane. Recovered enantiomerically enriched 2k:
66%. Appearance: pale yellow solid. 1H NMR (CDCl3) d 7.67 (dd,
J = 1.4, 7.0 Hz, 2H), 7.60 (m, 1H), 7.40–7.56 (m, 4H), 7.21–7.30
(m, 3H), 7.16 (t, J = 7.5 Hz, 2H), 6.81 (d, 7.0 Hz, 2H), 6.69 (s,
1H), 3.74 (d, J = 13.0 Hz, 1H), 3.53 (d, J = 13.0 Hz, 1H). 13C
NMR (CDCl3) d 168.6, 132.5, 132.40, 132.35, 130.6, 129.8, 129.4,
128.8, 128.6, 128.3, 128.0, 127.9, 127.7, 127.4, 126.9, 125.0, 117.2,
101.6, 61.6, 43.8. HRMS: C24H17BrN2O [M + K]+ calcd.: 451.0416,
found: 451.0410. [a]D23 −205.0 (10 mg mL−1 CHCl3, 93% ee). HPLC:
Daicel Chiralcel OD column [hexane–iPrOH (98 : 2)]; flow rate
1.0 mL min−1 (s3f = 9.2 min; s2k,minor = 21.4 min; s2k,major = 25.6 min).
1-Benzyl-5-bromoisoquinoline (3e). The title compound was
isolated from the asymmetric destruction of Reissert compound
2j. FC conditions: SiO2, eluent: gradual polarity change from
CH2Cl2 to 10% Et2O in CH2Cl2. Appearance: white solid. 1H
NMR (CDCl3) d 8.62 (d, J = 6.0 Hz, 1H), 8.14 (d, J = 8.5 Hz,
1H), 7.95 (d, J = 6.0 Hz, 1H), 7.93 (d, J = 7.5 Hz, 1H), 7.39 (t, J =
7.8 Hz, 1H), 7.23–7.31 (m, 4H), 7.16–7.23 (m, 1H), 4.71 (s, 2H).
13C NMR (CDCl3) d 160.5, 143.4, 139.1, 135.7, 133.6, 128.6, 128.5,
128.2, 127.5, 126.4, 125.6, 122.4, 118.7, 42.2. HRMS: C16H12BrN
[M + H]+ calcd.: 298.0226, found: 298.0228.
1-Benzyl-4-bromoisoquinoline (3f). The title compound was
isolated from the asymmetric destruction of Reissert compound
2k. FC conditions: SiO2, eluent: 15% Et2O in hexane. Appearance:
white solid. 1H NMR (CDCl3): d 8.69 (s, 1H), 8.18 (d, J = 8.5 Hz,
1H), 8.14 (d, J = 8.5 Hz, 1H), 7.75 (ddd, J = 1.1, 6.9, 8.2 Hz,
1H), 7.58 (ddd, J = 1.1, 7.0, 8.2 Hz, 1H), 7.22–7.30 (m, 4H),
7.18 (m, 1H), 4.63 (s, 2H). 13C NMR (CDCl3): d 159.7, 143.7,
138.9, 135.1, 131.1, 128.6, 128.5, 128.3, 128.1, 126.7, 126.4, 126.2,
118.5, 41.8. HRMS: C16H12BrN [M + H]+ calcd.: 298.0226, found:
298.0219.
Preparation of isoquinolines 3a–f. The isoquinolines 3a–f were
isolated from asymmetric destruction of the corresponding 1-
benzylated Reissert compounds performed as described above.
1-Benzylisoquinoline (3a). The title compound was isolated
from the asymmetric destruction of Reissert compound 2a. FC
conditions: SiO2, eluent: 20% EtOAc in hexane. Appearance: pale
yellow oil. 1H NMR (CDCl3) d 8.50 (d, J = 5.7 Hz, 1H), 8.14 (d,
J = 8.6 Hz, 1H), 7.79 (d, J = 8.1 Hz, 1H), 7.62 (t, J = 7.0 Hz,
1H), 7.47–7.58 (m, 2H), 7.21–7.32 (m, 4H), 7.17 (t, J = 7.0 Hz,
1H), 4.67 (s, 2H). 13C NMR (CDCl3) d 160.1, 142.0, 139.4, 136.5,
129.8, 128.6, 128.55, 128.47, 127.3, 127.2, 126.2, 125.8, 119.8, 42.1.
HRMS: C16H13N [M + H]+ calcd.: 220.1121, found: 220.1129.
Acknowledgements
This work was made possible by a grant from The Danish National
Research Foundation.
References
1-(4-Methoxy)benzylisoquinoline (3b). The title compound
was isolated from the asymmetric destruction of Reissert com-
pound 2g. FC conditions: SiO2, eluent: 5% Et2O–CH2Cl2. Ap-
1 (a) A. I. Meyers, D. A. Dickman and M. Boes, Tetrahedron, 1987, 43,
5095; (b) A. R. Katritzky, S. Rachwal and B. Rachwal, Tetrahedron,
1996, 52, 15031; (c) J. Royer, M. Bonin and L. Micouin, Chem. Rev.,
2004, 104, 2311; (d) M. Chrzanowska and M. D. Rozwadowska, Chem.
Rev., 2004, 104, 3341.
1
pearance: white solid. H NMR (CDCl3) d 8.49 (d, J = 5.7 Hz,
1H), 8.16 (d, J = 8.5 Hz, 1H), 7.80 (d, J = 8.2 Hz, 1H), 7.63 (ddd,
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app
fast
13 The enantiomeric ratio (er) is expected to change as: er = exp((k
−
app
slow
4 A. Reissert, Ber. Dtsch. Chem. Ges., 1905, 38, 3415.
k
) [C]t), where [C] is the concentration of the phase-transfer
5 For examples on racemic addition of electrophiles to Reissert com-
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511; (b) L. R. Walters, E. G. Podrebarac and W. E. McEven, J. Org.
Chem., 1961, 26, 1161; (c) J. M. Wefer and F. D. Popp, J. Org. Chem.,
1967, 32, 1999; (d) M. Makosza, Tetrahedron Lett., 1969, 9, 677; (e) R.
Piccirilli and F. D. Popp, Can. J. Chem., 19690, 47, 3261; (f) J. L.
Neumeyer, K. H. Oh, K. K. Weinhardt and B. R. Neustadt, J. Org.
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catalyst in the organic phase and t is time. For the derivation of this
expressionsee ESI.† See also the mechanistic discussion below.
14 kapp = (kꢀ1K1 + kꢀ2K2) and k = (kꢀ3K3 + kꢀ4K4), where kꢀy are the rate
app
slow
fast
constants for the reaction 7 → 8 and Ky are the equilibrium constants
for the reaction 2a → 7 (y = 1–4). See also ESI.
15 The decomposition of 7 by a simultaneous loss of benzoate and HCN
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16 (a) P. Vachal and E. N. Jacobsen, Org. Lett., 2000, 2, 867; (b) M. S.
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6 See references: 3g,5a,5d,5f –h,5j,5m,5n; see also: (a) M. S. Taylor and
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8 Alternative approaches to non-racemic 1-substituted Reissert com-
pounds have previously been reported. For an enantioselective Reissert
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H. Ratni, M. Kanai and M. Shibasaki, J. Am. Chem. Soc., 2001, 123,
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9 Although only to a minor extent, decomposition of substrate 1
(R1 = alkyl, Ar) to give 1-cyanoisoquinoline was also observed
under the applied alkaline conditions and in the presence of air. See:
(a) M. D. Rozwadowska and D. Bro´zda, Can. J. Chem., 1980, 58, 1239;
18 (a) A. W. Bridge, M. B. Hursthouse, C. W. Lehmann, D. J. Lythgoe
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21 S.-s. Jew, M.-S. Yoo, B.-S. Jeong, I. Y. Park and H.-g. Park, Org. Lett.,
2002, 4, 4245.
22 S.-s. Jew, B.-S. Jeong, M.-S. Yoo, H. Huh and H.-g. Park, Chem.
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2974 | Org. Biomol. Chem., 2007, 5, 2966–2974
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