N-methylimidazole promotes the reaction of homophthalic anhydride with imines

Article abstract of DOI:10.1021/jo501316m

The addition of N-methylimidazole (NMI) to the reaction of homophthalic anhydride with imines such as pyridine-3-carboxaldehyde-N-trifluoroethylimine (9) reduces the amount of elimination byproduct and improves the yield of the formal cycloadduct, tetrahydroisoquinolonic carboxylate 10. Carboxanilides of such compounds are of interest as potential antimalarial agents. A mechanism that rationalizes the role of NMI is proposed, and a gram-scale procedure for the synthesis and resolution of 10 is also described.

Full text of DOI:10.1021/jo501316m

Article
pubs.acs.org/joc
Open Access on 07/18/2015
N‑Methylimidazole Promotes the Reaction of Homophthalic
Anhydride with Imines
Jian Liu,† Zheng Wang,† Aaron Levin,† Thomas J. Emge,† Paul R. Rablen,‡ David M. Floyd,†
and Spencer Knapp*,†
†Department of Chemistry & Chemical Biology, Rutgers The State University of New Jersey, 610 Taylor Road, Piscataway, New
Jersey 08854, United States
‡Department of Chemistry and Biochemistry, Swarthmore College, Swarthmore, Pennsylvania 19081, United States
S
* Supporting Information
ABSTRACT: The addition of N-methylimidazole (NMI) to
the reaction of homophthalic anhydride with imines such as
pyridine-3-carboxaldehyde-N-trifluoroethylimine (9) reduces
the amount of elimination byproduct and improves the yield of
the formal cycloadduct, tetrahydroisoquinolonic carboxylate
10. Carboxanilides of such compounds are of interest as
potential antimalarial agents. A mechanism that rationalizes the role of NMI is proposed, and a gram-scale procedure for the
synthesis and resolution of 10 is also described.
(HPA) 4 with aldimines 5 (Scheme 1).4 The reaction is
commonly thought to proceed by way of a Mannich intermediate
INTRODUCTION
Malaria persists as a global health risk, with roughly 200 million
■
cases of the disease reported in 2012, accompanied by an
estimated 627 000 deaths.1 Antimalarial drugs remain among the
Scheme 1. Formal Cycloaddition of Homophthalic Anhydride
with Aldimines
most effective tools for defeating the Plasmodium agent, and new
treatments are continually required as resistance to more
traditional drugs such as artemisinin sets in.2 Phenotypic
screening has proven to be a good source of lead compounds
for this purpose, and a recent campaign examining more than
300 000 compounds for activity against P. falciparum in human
erythrocytes revealed among the actives a series of tetrahy-
droisoquinolonic carboxanilides related to 1.3 Hit-to-lead studies
have further identified carboxanilides 2 and 3 as worthy of further
development.
We have undertaken an investigation of methods to improve
existing syntheses of this class of compounds and can report that
N-methylimidazole has proven beneficial as a promoter of the
formal cycloaddition reaction of homophthalic anhydride with
aldimines.
6, the amino group of which subsequently closes upon the
anhydride carbonyl group in a Perkin-analogous process leading
to lactam acid 8.5 Alternatively, a more direct cycloaddition
pathway leading to intermediate 7 or its tautomer has been
considered.6 The reaction often goes well without additives or
catalysts, but various improvements have been recommen-
ded.4,6,7 In our specific case with the N-2,2,2-trifluoroethylimine
derived from pyridine-3-carboxaldehyde (i.e., 9, Table 1), the
RESULTS AND DISCUSSION
■
A variety of methods have been described for the synthesis of 1-
oxo-2-alkyl-3-aryl-1,2,3,4-tetrahydroisoquinoline-4-carboxylic
acids 8 by formal cycloaddition of homophthalic anhydride
Received: June 12, 2014
Published: July 18, 2014
© 2014 American Chemical Society
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Table 1. Effect of Additives and Solvent on the Apparent Yield of 1-Oxo-2-(2,2,2-trifluoroethyl)-3-(3-pyridyl)-1,2,3,4-
tetrahydroisoquinoline-4-carboxylic Acids 10
a
base (equiv)
pKa
solvent
CHCl3
NMR yield (trans:cis)
no base
47% (2.2:1)
pyridine (1.0)
5.2
8.8
7.6
6.6
7.4
9.2
″
8.0
9.6
4.8
7.0
″
″
″
″
″
″
″
45% (1:1)
b
DABCO (1.0)
b
b
b
2,4,6-collidine (1.0)
N,N-diethylaniline (1.0)
N-methylmorpholine (1.0)
4-(dimethylamino)pyridine (1.0)
4-(dimethylamino)pyridine (1.0)
4-(4-morpholino)pyridine (1.0)
4(1-pyrrolidino)pyridine (1.0)
HOAc (1.0)
55%
b
CH3CN
CHCl3
47%
″
″
36%
50% (4:1)
63%
N-methylimidazole, NMI (1.0)
NMI (1.5)
″
68%
NMI (0.5)
″
″
65%
NMI (2.0)
″
″
78%
NMI (5.0)
″
″
″
″
″
53%
b
NMI (neat)
b
NMI (1.0)
toluene
NMI (1.0)
″
″
CH2Cl2
66%
c
b
NMI (1.0)
14 other solvents
c
a
b
Approximate pKa of conjugate acid. Poor yield and/or messy reaction mixture. Solvents tried: methyl acetate, ethyl acetate, isopropyl acetate,
isobutyl acetate, n-butyl acetate, ethyl lactate, dimethyl carbonate, diethyl carbonate, tetrahydrofuran, acetone, tert-butanol, acetonitrile, propionitrile,
and diethoxymethane.
reaction under several literature conditions led to large amounts
of an elimination pathway (see 12, Scheme 2) and associated
downstream educts and other byproducts, accompanied by only
modest yields of desired product 10. Aldimines of basic
heterocyclic carboxaldehydes were generally troublesome as
cycloaddition partners. We, therefore, set about screening
solvents and additives, including various weak bases and acyl
transfer promoters, as displayed in Table 1.
formation of the cis and trans products 10 (∼1.2:1 respectively, as
their NMI salts) was complete, according to the presence of
diagnostic signals for their H-3 and H-4 protons. In particular,
trans-10 shows narrow doublets (J < 1 Hz) at 5.6 and 3.9 ppm,
and cis-10 shows wider doublets (J = 6 Hz) at 5.3 and 4.8 ppm.
These values are fully consistent with our spectra of isolated cis/
trans mixtures and those reported for analogous 1-oxo-2-alkyl-3-
aryl-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acids found in
the literature.4 Also apparent was the multiplet for trifluoroethyl-
amine at 3.2 ppm, indicative of the elimination pathway (Scheme
2), and some unreacted imine 9. In addition, two sets of
(initially) unassigned wide doublets were observed at 4.21 and
4.83 ppm (J = 12.0 Hz), and at 4.59 and 4.37 ppm (J = 12.6 Hz)
in a 3:1 respective ratio. A gCOSY spectrum of the reaction
mixture taken after 40 min of reaction time in situ (Figure 1)
shows the expected cross-peaks for coupling of all eight doublets
in the region of 3−6 ppm, as well as cross-peaks for the geminal
dq signals (two each) for the −CH2CF3 substituents of cis- and
trans-10.
Over the next 24 h at room temperature in dichloromethane-
d2 solution, the cis/trans mixture of products 10 isomerized
exclusively to the more stable trans-10 (as the NMI salt), a
process promoted by NMI that we also observed later in gram-
scale runs. The wide doublets disappeared, and a new singlet at
5.3 ppm became evident and grew in further over 48 h. From a
later gram-scale reaction, we isolated this same byproduct,
dibenzodihydroisocoumarin carboxylic acid 15 (diagnostic
singlet at 5.3 ppm) as its NMI salt, and confirmed its structure
and trans stereochemistry by X-ray crystallography (see the
By examining the crude reaction products by proton NMR
spectroscopy in the presence of a known amount of an internal
standard, 2,6-di-tert-butyl-4-methylphenol (BHT), and integrat-
ing the appropriate signals, the approximate reaction yields of the
desired trans and cis products (10, combined) could be
determined. Apparent yields for the reaction in chloroform
solution without additive or with an equiv of acetic acid hovered
around 50%. Among the various additives examined, 4-(N,N-
dimethylamino)pyridine led to a slight improvement (55%),
whereas other amines of similar or lower basicity gave poorer
yields and/or messier reactions. N-Methylimidazole (NMI), on
the other hand, with a pKa ∼ 7.0 (for NMI·H+),8 gave an
improved yield (63%) at 1 equiv, and this could be increased to
78% at 2 equiv. Greater or lesser amounts of NMI did not help
further. A wide variety of solvents were also screened. Of these,
only dichloromethane gave yields comparable to those with
chloroform, and thus, dichloromethane was selected as the
preferred solvent and 2 equiv of NMI as the preferred additive.
The reaction of HPA 4 and imine 9 with 2 equiv of NMI in
dichloromethane-d2 solution was monitored in situ by proton
NMR spectroscopy at room temperature. Within 2.5 min,
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Experimental Section). This type of HPA adduct has been
reported previously9 and is a downstream result of the undesired
Knoevenagel pathway illustrated in Scheme 2.
Scheme 2. Proposed Knoevenagel Byproduct 12 and
Intermediates Leading to Dibenzodihydroisocoumarin 15
According to the mechanism proposed in Scheme 2,
Knoevenagel product 12 can form from Mannich adduct 11 by
loss of 2,2,2-trifluoroethylamine. Conjugate addition of a second
equiv of HPA leads to two-to-one adduct 13, and then
intramolecular C-acylation onto one of the anhydride carbonyl
groups gives spiroanhydride 14 as a potential mixture of up to
four diastereomers. Decarboxylation and O-cyclization furnishes
15. Spiro anhydrides 14 have not been previously observed in
reactions of this type, but could account for the unassigned wide
doublets observed by proton NMR early in the reaction course.
Calculational determination [Gaussian 09, B3LYP/6-31G(d)]
of the structures of the two trans isomers of 14 was carried out,
along with a calculation of the expected chemical shifts and
coupling constants of the ring methines. The results are displayed
in Figure 2, and the calculated structures and methodological
details are provided in the Experimental Section and the
Supporting Information. A close match is obtained between
the calculated chemical shifts of the two trans-14 isomers and the
observed values, and the respective calculated, unusually wide,
vicinal coupling constants also match quite well with the
observed J values. On the basis of these calculational results, the
proton NMR observations over the time course of the reaction,
and on the presumed mechanism (Scheme 2) for formation of
15, the wide doublets are assigned to pseudo-trans-diaxial vicinal
H’s of intermediate trans spiro anhydrides 14.
An additional change in reaction conditions was made for the
gram-scale preparation of 10: by conducting the initial reaction at
−30 °C, the Knoevenagel pathway was suppressed almost
Figure 1. Reaction of homophthalic anhydride with NMI and imine 9 after 40 min. gCOSY cross-peaks for the wide doublets from the two spiro
anhydride ring H’s are designated, respectively, c (red) and d (red). Cross-peaks for the respective ring proton doublets (a and b) and the −CH2CF3
doublets-of-quartets (a’ and b’) signals for trans- and cis-10 are also designated.
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and the main side reaction, Knoevenagel-type elimination
(Scheme 4). Should NMI intercept Mannich intermediate 11,
Scheme 4. Proposed Role of NMI in the Reaction of HPA with
Aldimines
Figure 2. Calculated and observed chemical shifts and vicinal coupling
constants for the spiro anhydrides 14.
entirely (Scheme 3). The reaction mixture was then stirred (NMI
is still present) for a day, during which time the cis/trans mixture
Scheme 3. Optimized Conditions for Gram-Scale Synthesis of
10
acting as an acyl transfer promoter,10,11 the resulting activated N-
acylimidazolium intermediate, 16, is well-suited for ring closure
to give desired product 17. In contrast, the elimination process
would be suppressed, inasmuch as full alignment and conjugation
of the newly forming π bond with the π systems of the benzo ring
and the carbonyl group, a situation obtaining in 11, is weakened
by σ bond rotation in 16. Furthermore, enolization of the
anhydride carbonyl group, should this be prelude to elimination,
is favored in 11, but not for the carbonyl group in 16. 4-(N,N-
Dimethylamino)pyridine and related pyridines also promote the
reaction (Table 1), possibly as a result of their well-established
acyl transfer promoting property,12,13 whereas organic bases
without this characteristic, such as N-methylmorpholine, N,N-
diethylaniline, and 2,4,6-collidine, are ineffective.
We also applied the new reaction conditions (−30 °C, 2 equiv
of NMI in dichloromethane solution) for the gram-scale
synthesis of three other 1-oxo-2-alkyl/aryl-3-aryl-1,2,3,4-tetrahy-
droisoquinoline-4-carboxylic acids of interest to us: 19, 20, and
21 (Chart 1). Preparation of the appropriate aldimine coupling
Chart 1. Additional Examples of NMI Promoted HPA/
Aldimine Cycloadditions
was cleanly converted to all-trans. NMI is well-suited for this
isomerization at room temperature; analogous treatment of the
mixture with triethylamine led to no isomerization. Adjustment
of the pH to near the isoelectric point of the product (∼pH 4.5)
caused it to precipitate, and filtration gave 10 in 84% overall yield.
What is the role of NMI in this formal cycloaddition, and how
does it improve the reaction? Possibly, NMI benefits the reaction
by affecting the balance between Perkin-analogous ring closure
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1H NMR spectroscopy. The well-separated H-3 signals for respective
trans- and cis-tetrahydroisoquinolone carboxylate products 10 appear at
5.67 ppm (d, J = 0.9 Hz) and 5.41 ppm (d, J = 6.0 Hz), and the methyl (3
H) singlet of BHT appears at 2.23 ppm. The measured integral of the
latter is corrected by the deviation of the molar equivalent amount of
BHT from 0.333; here, 3.22 (measured) is corrected to 3.11. The sum of
the measured integrals of the respective H-3 signals, in this case, 1.00 and
0.46, is divided into the corrected integral of BHT to give the apparent
crude yield (here, 1.46:3.11 = 47%). Analogous measurements on
reactions with added promoters gave the cycloadduct trans/cis ratios and
the apparent yields shown in Table 1. In several cases, the initial cis/trans
mixtures of 10 isomerized over the 16 h to all-trans.
partners is described in the Experimental Section. Products 19
and 20 are the precursors to carboxanilides 1 and 3, respectively.
Compound 21 has been reported previously.14,15
Finally, we developed an unusual, but effective, procedure for
resolving racemic trans-10 (Scheme 5) to provide the desired
Scheme 5. Resolution of Racemic 10
(E)-2,2,2-Trifluoro-N-(pyridin-3-ylmethylene)ethanamine (9).
Aqueous sodium hydroxide (11.8 g, 295 mmol) was added slowly to a
cooled (ice bath) mixture of 2,2,2-trifluoroethylamine hydrochloride
(39.8 g, 295 mmol), 3-pyridinecarboxaldehyde (21 g, 196 mmol), and
toluene (100 mL) at 0 °C. The reaction mixture was stirred at 0 °C for 2
h, then at 23 °C for 15 h. The toluene layer was separated, and the
aqueous layer was washed with additional toluene (6 × 50 mL). The
combined organic solution was dried over sodium sulfate and
concentrated to afford 34.57 g (94%) of imine 9 as a pale yellow oil.
1H NMR (300 MHz, CDCl3) δ 8.90 (d, 1 H, J = 2.1 Hz), 8.72 (dd, 1 H, J
= 4.8 and 1.8 Hz), 8.41 (br s, 1 H), 8.20 (dt, 1 H, J = 7.8 and 1.8 Hz), 7.39
(dd, 1 H, J = 8.1 and 4.8 Hz), 4.18 (qd, 2 H, J = 9.3 and 1.5 Hz); 13C
NMR (75.4 MHz, CDCl3) δ 164.0, 152.5, 150.71, 134.8, 130.8, 124.3 (q,
J = 275 Hz), 123.8, 61.6 (q, J = 29.7 Hz); HR-ESI-MS [M + H]+ calcd for
C8H8F3N2, 189.0634; found, 189.0635.
(+)-(3S,4S) enantiomer. A suspension of racemic 10 and 2 equiv
of commercial (1S,2S)-(+)-1-amino-2-indanol (22) in a 1:1
mixture of heptane and propionitrile was digested at reflux,
cooled, and then filtered. The resulting solid was subjected to
another digestion, and then the collected product was analyzed
by proton NMR spectroscopy. Integration indicated that this salt
comprises a two-to-one complex of 22 with 10. Acidification with
acetic acid, extraction, and then exhaustive concentration
produced (+)-10 (71% overall), mp 134−137 °C, enantiomeri-
cally pure according to chiral HPLC analysis. Likewise, the use of
(1R,2R)-(+)-1-amino-2-indanol afforded 71% of the (−)
enantiomer of 10, mp 135−137 °C, also enantiomerically pure
according to chiral HPLC analysis. The absolute configuration of
the (−)-10 enantiomer was established unambiguously as
(2R,3R) by X-ray crystallographic analysis of its salt with (R)-
(−)-2-amino-1-phenylethanol. Details of these procedures are
provided in the Experimental Section and in the Supporting
Information.
(3S*,4S*)-1-Oxo-3-(pyridin-3-yl)-2-(2,2,2-trifluoroethyl)-
1,2,3,4-tetrahydroisoquinoline-4-carboxylic Acid (Racemic
trans-10). A solution of aldimine 9 (1.00 g, 5.3 mmol) and N-
methylimidazole (0.87 g, 10.6 mmol) in 16 mL of dichloromethane was
stirred for 40 min at 23 °C, and then was cooled to −30 °C (internal
temperature) by using a dry ice acetone bath. Solid homophthalic
anhydride (0.86 g, 5.3 mmol) was added in one aliquot, and the solid was
observed to dissolve in less than 1 min. The reaction mixture was stirred
for 2.5 h at −30 °C, and then the cooling bath was removed and the
reaction mixture was allowed to come to room temperature and stirred
for a total of 48 h. Saturated aqueous sodium chloride solution (30 mL)
was added, and the resulting reaction mixture was brought to pH 4.5
(monitored by pH meter) by addition of concentrated hydrochloric acid
(37%, ∼0.88 mL). The resulting suspension was stirred for 12 h and
then filtered. The precipitate was collected by filtration, and the solid
product was washed with ice cold water (2 × 15 mL) and pumped to
dryness, affording carboxylic acid trans-10 (1.55 g, 84%), mp 229.1−
230.5 °C: 1H NMR (300 MHz, MeOH-d4) δ 8.40 (dd, 1 H, J = 4.8 and
1.5 Hz), 8.36 (d, 1 H, J = 2.1 Hz), 8.11−8.08 (m, 1 H), 7.56−7.45 (m, 3
H), 7.32 (dd, 1 H, J = 8.1 and 4.8 Hz), 7.23−7.26 (m, 1 H), 5.67 (d, 1 H,
J = 1.5 Hz), 4.57 (dq, 1 H, J = 15 and 9.0 Hz), 4.18 (d, 1 H, J = 1.5 Hz),
4.12 (dq, 1 H, J = 15 and 9.0 Hz); 13C NMR (75.4 MHz, DMSO-d6) δ
172.1, 164.6, 149.4, 148.2, 134.8, 134.4, 133.5, 130.3, 128.9, 128.6, 128.0,
126.7 (q, J = 210 Hz), 124.1, 123.9, 61.3, 51.0, 47.2 (q, J = 24.6 Hz); HR-
ESI-MS [M + H]+ calcd for C17H14F3N2O3, 351.0949; found, 351.0951.
2-Methyl-N-(thiophen-2-ylmethylene)propan-1-amine. Thio-
phene-2-carboxaldehyde (6.70 g, 60.6 mmol) was added to a solution of
isobutylamine (8.91 mL, 90 mmol) in 28 mL of acetonitrile, and the
solution was stirred at 23 °C for 15 h. Concentration afforded 9.6 g
CONCLUSION
■
N-Methylimidazole is effective as an additive in the formal
cycloaddition reactions of aldimines with homophthalic
anhydride, increasing both the yield and the selectivity
(cyclization versus elimination), and also promoting the
isomerization of cis/trans mixtures of product to all-trans. NMI
may act in this instance as an acyl transfer agent, intercepting the
Mannich intermediate, e.g., 11, and promoting its ring closure. 1-
Oxo-2-alkyl/aryl-3-aryl-1,2,3,4-tetrahydroisoquinoline-4-carbox-
ylic acids 10, 19, 20, and 21 have been prepared on a gram scale
by this method.
1
(96%) of the title compound as a yellow oil: H NMR (300 MHz,
MeOH-d4) δ 8.34 (d, 1 H, J = 1.2 Hz), 7.51 (dt, 1 H, J = 5.1 and 1.2 Hz),
7.41 (dd, 1 H, J = 3.6 and 1.2 Hz), 7.09 (dd, 1 H, J = 4.8 and 3.6 Hz), 3.34
(dd, 1 H, J = 6.6 and 1.2 Hz), 1.95 (app nonet, 1 H, J = 6.6 Hz), 0.92 (d, 6
H, J = 6.6 Hz); 13C NMR (75.4 MHz, MeOH-d4, δ 155.7, 141.5, 131.4,
129.1, 127.3, 68.5, 29.2, 19.6; HR-ESI-MS [M + H]+ calcd for C9H14NS,
168.0849; found, 168.0850.
(3S*,4S*)-2-Isobutyl-1-oxo-3-(thiophen-2-yl)-1,2,3,4-tetra-
hydroisoquinoline-4-carboxylic Acid (19). Homophthalic anhy-
dride (0.969 g, 5.98 mmol) was added to a solution of 2-methyl-N-
(thiophen-2-ylmethylene)propan-1-amine (1.00 g, 5.98 mmol) and N-
methylimidazole (0.982 g, 12.0 mmol) in 17.6 mL of dichloromethane at
−30 °C as described above. The reaction mixture was stirred at −30 °C
for 2.5 h and then at 23 °C for 24 h, concentrated, and then
EXPERIMENTAL SECTION
■
Estimation of Crude Cycloaddition Yields by 1H NMR
Spectroscopy with BHT as Internal Standard. This example of
the standard procedure used no additive. A stirred solution of aldimine 9
(50.0 mg, 0.270 mmol, 1 equiv) in 2 mL of chloroform was treated with
homophthalic anhydride 4 (43.7 mg, 0.270 mmol, 1 equiv) in one
aliquot. After 16 h, the reaction was concentrated and the residue was
dissolved in 2 mL of MeOH-d4. Approximately 0.333 molar equiv of 2,6-
di-tert-butyl-4-methylphenol (BHT) was added, in this case, 20.5 mg
(0.093 mmol, 0.344 equiv), and the resulting solution was analyzed by
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chromatographed on silica by using 20:1 hexanes/acetic acid and then
concentrated. Trituration of the residue over 16 h with 200 mL of ether
12:8:1 hexanes/ethyl acetate/acetic acid as the eluant to afford 1.67 g
(85%) of carboxylic acid 19, mp 165−168 °C: H NMR (300 MHz,
gave a supernatant that, upon standing, deposited 580 mg of N-
methylimidazolium salt of 15 as a tan solid: H NMR (300 MHz,
1
1
DMSO-d6) δ 13.16 (s, 1 H), 7.92 (dd, 1 H, J = 7.8 and 1.5 Hz), 7.49 (td,
1 H, J = 7.2 and 1.5 Hz), 7.42 (td, 1 H J = 7.5 and 1.5 Hz), 7.35 (dd, 1 H, J
= 7.2 and 1.5 Hz), 7.26 (dd, 1 H, J = 4.8 and 1.5 Hz), 6.99 (dd, 1 H, J =
3.3 and 1.5 Hz), 6.86 (dd, 1 H, J = 4.8 and 3.3 Hz), 5.55 (d, 1 H, J = 1.5
Hz), 4.23 (d, 1 H, J = 1.5 Hz), 3.81 (dd, J = 13.2 and 9.3 Hz), 2.68 (dd, 1
H, J = 13.2 and 5.4 Hz), 1.97−2.11 (m, 1 H), 0.90 (d, 3 H, J = 6.9 Hz),
0.82 (d, 3 H, J = 6.9 Hz); 13C NMR (75.4 MHz, DMSO-d6) δ 172.2,
163.2, 143.7, 134.5, 132.3, 130.4, 129.4, 128.4, 127.5, 127.0, 126.6, 125.9,
58.2, 52.8, 51.0, 27.3, 20.6 (2 C); HR-ESI-MS [M + H]+ calcd for
C18H20NO3S, 330.1167; found, 330.1161.
(E)-N-((1H-Pyrazol-4-yl)methylene)-2,2,2-trifluoro-
ethanamine. Solid 4-pyrazolecarboxaldehyde hydrochloride (10.0 g,
76 mmol), prepared by the literature method,16 was added to a cooled
(ice bath) solution of 2,2,2-trifluoroethylamine hydrochloride (15.2 g,
113 mmol) in 36 mL of acetonitrile, followed by triethylamine (31.5 mL,
226 mmol). The resulting reaction mixture was allowed to warm to 23
°C and was stirred for an additional 15 h. The reaction mixture was
filtered, and the solids were washed with 50 mL of acetonitrile. The
organic solution was concentrated and then digested with ethyl ether (3
× 30 mL). Concentration of the ether supernatant gave 12.0 g (90%) of
the aldimine as a white foam. 1H NMR (400 MHz, MeOH-d4) δ 8.42 (d,
1 H J = 1.5 Hz), 8.06 (br s, 2 H), 4.12 (qd, 2 H, J = 9.6 and 1.5 Hz); 13C
NMR (100.6 MHz, MeOH-d4) δ 161.1, 138.6 (br), 131.2 (br), 125.1 (q,
J = 274 Hz), 119.5, 60.7 (q, J = 30.5 Hz); HR-ESI-MS [M + H]+ calcd for
C6H7F3N3, 178.0587; found, 178.0588.
(3S*,4S*)-1-Oxo-3-(1H-pyrazol-4-yl)-2-(2,2,2-trifluoroethyl)-
1,2,3,4-tetrahydroisoquinoline-4-carboxylic Acid (20). Homo-
phthalic anhydride 4 (0.271 g, 1.67 mmol) was added to a solution of
(E)-N-[(1H-pyrazol-4-yl)methylene]-2,2,2-trifluoroethanamine (0.296
g, 1.67 mmol) and N-methylimidazole (0.982 g, 3.34 mmol) in 5 mL of
dichloromethane and 1 mL of acetonitrile at −30 °C as described above.
The reaction mixture was stirred at −30 °C for 2.5 h and at 23 °C for 48
h, and then concentrated. The residue was purified by column
chromatography on silica by using 20:1 hexanes/acetic acid and then
12:8:1 hexanes/ethyl acetate/acetic acid as the eluant to afford title
compound 20 as a white solid (0.365 g, 64% yield), mp 268.5−270.3 °C:
1H NMR (400 MHz, MeOH-d4) δ 8.05 (d, 1 H, J = 7.5), 7.54 (td, 1 H, J
= 7.5 and 1.0 Hz), 7.47 (td, 1 H, J = 8.0 and 1.5 Hz), 7.32 (d, 1 H, J = 7.5
Hz), 7.26 (br s, 2 H), 5.11 (d, 1 H, J = 1.5 Hz), 4.68 (dq, 1 H, J = 15.5 and
9.5 Hz), 4.13 (d, 1 H, J = 1.5 Hz), 3.83 (dq, 1 H, J = 15.5 and 9.5 Hz); 13C
NMR (100.6 MHz, DMSO-d6) δ 172.2, 165.3, 135.1, 133.0, 132.0,
129.8, 128.3, 128.2, 127.8, 124.8 (q, J = 278 Hz), 119.4, 117.0, 56.2, 51.0,
46.5 (q, J = 34 Hz); HR-ESI-MS [M + H]+ calcd for C15H13F3N3O3,
340.0909; found, 340.0900.
MeOH-d4) δ 8.50 (d, 1 H, J = 2.4 Hz,), 8.29−8.33 (m, 2 H), 8.03 (s, 1
H), 7.93 (dd, 1 H, J = 1.5 and 7.65 Hz), 7.76 (dt, 1 H, J = 1.5 and 8.1 Hz),
7.67 (d, 1 H, J = 7.8 Hz), 7.61 (td, 1 H, J = 2.1 and 7.8 Hz), 7.54 (dt, 1 H,
J = 1.2 and 7.5 Hz), 7.43 (dt, 1 H, J = 1.5 and 7.6 Hz), 7.34 (dt, 1 H, J =
1.5 and 7.5 Hz), 7.30 (dd, 1 H, J = 1.5 and 7.5 Hz), 7.20−7.24 (m, 2 H),
7.15 (t, 1 H, J = 1.5 Hz), 5.28 (s, 1 H), 3.98 (d, 1 H, J = 1.5 Hz), 3.80 (s, 3
H); C13 NMR (75.6 MHz, DMSO-d6) δ 173.1, 161.3, 149.7, 148.7,
148.4, 138.2, 136.4, 136.1, 136.0, 135.5, 132.6, 131.3, 130.3, 130.1,
129.01, 128.8, 128.3, 128.1, 124.0, 123.5, 122.7, 121.2, 121.1, 110.4, 51.6,
37.4, 33.35. A sample crystallized from isopropanol gave free acid 15 (i-
PrOH solvate), mp 170−171.3 °C: HR-ESI-MS [M + H]+ calcd for
C23H16NO4, 370.1079; found, 370.1059. These crystals were suitable for
single-crystal X-ray analysis.
2,2,2-Trifluoroethylamine. A mixture of 10 mg of 2,2,2-
trifluoroethylammonium chloride, 15 mg of solid sodium hydroxide,
and 1.5 mL of dichloromethane-d2 was stirred for 10 min. The
supernatant, which contains the free base, was examined by NMR
1
spectroscopy: H NMR (300 MHz, dichloromethane-d2) δ 3.20 (app
sextet, 2 H, J = 8.7 Hz), 1.31 (br s, 2 H).
Resolution of racemic 10. A suspension of racemic 10 (9.0 g, 25.7
mmol, prepared as described above) and 7.68 g (50 mmol, 1.95 equiv) of
(1S,2S)-(+)-trans-1-amino-2-indanol (22) in 270 mL of 1:1 propioni-
trile/heptane was heated at reflux (82 °C internal temperature) for 3.5 h.
The resulting suspension was cooled to 23 °C over 3 h and filtered, and
the solids were washed with 102 mL of 1:1 propionitrile/heptane. The
solids were digested again with 270 mL of the same solvent mixture, and
after filtration and rinsing as before, the recovered solids were dried at 50
°C for 15 h to afford 7.70 g of the chiral 2:1 salt, mp 176−178 °C: 1H
NMR (500 MHz, MeOH-d4) δ 8.33 (d, 2 H, J = 5.0 Hz), 8.01 (dd, 1 H, J
= 7.5 and 1.5 Hz), 7.55 (dd, 1 H, J = 7.0 and 3 Hz), 7.42 (td, 1 H, J = 7.5
and 1.5 Hz), 7.34−7.40 (m, 3 H), 7.20−7.30 (m, 7 H), 7.14 (dd, 1 H, J =
7.5 and 0.5 Hz), 5.60 (s, 1 H), 4.30−4.40 (m,1 H), 3.75 (s, 1 H), 4.20−
4.30 (m, 5 H), 3.75 (s, 1 H), 3.28 (dd, 2 H, J = 16 and 6.5 Hz), 2.82 (dd, 2
H, J = 16 and 6.5 Hz). This product was dissolved in 300 mL of 9:1
water/acetic acid and stirred for 15 h. Extraction with ethyl acetate (4 ×
100 mL), followed by concentration in vacuo at 95 °C to remove traces
of acetic acid, gave 3.2 g (71% of theoretical) of resolved (+)-10, mp
134−137 °C: [α]2D0 + 60 (c 1.00, MeOH); analysis by chiral HPLC
(Chiral Pak IC, 250 × 4.6 mm, 5 μ; mobile phase 80:20 hexane/
isopropanol with 0.1% trifluoroacetic acid; flow rate 4 mL/min;
enantiomers baseline separated) indicated an er > 99.9. Anal. Calcd for
C17H13F3N2O3: C, 58.29; H, 3.74; F, 16.27; N, 8.00. Found: C, 58.20; H,
3.86; F, 16.00; N, 7.82.
By the identical procedure, but using instead (1R,2R)-(−)-trans-1-
amino-2-indanol, racemic trans acid 10 (234 mg, 0.66 mmol) was
converted to its 2:1 salt (173 mg, 80%), mp 176−178 °C. Liberation of
(−)-10 as above gave 82 mg (70% overall from racemic 10), mp 135−
137 °C: [α]2D0 − 61 (c 1.00, MeOH).
(3S*,4S*)-1-Oxo-2,3-diphenyl-1,2,3,4-tetrahydroisoquino-
line-4-carboxylic Acid (21).13,14 Homophthalic anhydride 4 (0.895 g,
5.52 mmol) was added to a solution of the commercial N-
benzylideneaniline (1.00 g, 5.52 mmol) and N-methylimidazole
(0.900 g, 11.0 mmol) in 16.2 mL of dichloromethane at −30 °C as
described above. The reaction mixture was stirred at −30 °C for 2.5 h
and then at 23 °C for 48 h, concentrated, and then chromatographed on
silica by using a gradient eluent of 20:1 hexanes/acetic acid through
12:8:1 hexanes/ethyl acetate/acetic acid to afford 1.14 g (60%) of
carboxylic acid 21. A sample crystallized from methanol had mp 224.2−
Determination of Absolute Stereochemistry of Resolved
(−)-10. A mixture of (−)-10 (200 mg, 0.57 mmol) and (R)-(−)-2-
amino-1-phenylethanol (80 mg, 0.58 mmol) in 2 mL of 1:1 isopropyl
alcohol/heptane was heated at reflux to produce a clear solution. The
solution was allowed to cool and rest at 23 °C overnight. The resulting
crystals were collected by filtration and washed with a small amount of
1:1 isopropyl alcohol/heptane to afford 109 mg of the 1:1 salt (also
contains 0.5 i-PrOH of crystallization), mp 112−114 °C: 1H NMR (500
MHz, MeOH-d4) δ 8.34 (dd, 2 H, J = 4.5 and 1.5 Hz), 8.08 (dd, 1 H, J =
7.5 and 1.5 Hz), 7.55 (dt, 1 H, J = 8.0 and 1.5 Hz), 7.29−7.45 (m, 6H),
7.25−7.28 (m, 1 H), 7.27 (dd, 1 H, J = 8 and 5 Hz), 7.14(d, 1 H, J = 7
Hz), 5.60 (s, 1 H), 4.83−4.86 (m, 1H), 4.24−4.24 (m, 2 H), 3.80−3.95
(m, 0.25 H, IPA), 3.77 (s, 1H), 3.09 (dd, 1 H, J = 12.5 and 1.5 Hz), 2.96
(dd, 1 H, J = 13 and 9.5 Hz), 1.14 (d, 1.5 H, IPA, J = 6 Hz). These crystals
proved suitable for X-ray analysis (see the Supporting Information).
Calculational Studies. All calculations were carried out by using the
Gaussian 09 software package.17 The geometries of the two
diastereomers of 14 were optimized by using the B3LYP/6-31G(d)
level of theory, followed by frequency calculations at the same level. The
226.5 °C, lit.14 mp 203−204 °C: H NMR (300 MHz, DMSO-d6) δ
1
13.21 (s, 1 H), 8.00 (d, 1 H, J = 6.9 Hz), 7.22−7.46 (m, 13 H), 5.71 (s, 1
H), 4.24 (s, 1 H); 13C NMR (75.4 MHz, DMSO-d6) δ 172.5, 163.1,
142.8, 139.7, 134.3, 132.8, 130.2, 129.6, 129.3 (2 C), 129.1 (2 C), 128.5,
127.9, 127.8, 127.0, 126.8 (2 C), 126.7 (2 C), 64.8, 51.6; HR-ESI-MS [M
+ H]+ calcd for C22H18NO3, 344.1289; found, 344.1293.
(11S*,12R*)-6-Oxo-11-(pyridin-3-yl)-11,12-dihydro-6H-
dibenzo[c,h]chromene-12-carboxylic Acid (15). The N-methyl-
imidazolium salt of 15 was obtained serendipitously from a large-scale
preparation of 10. A stirred solution of aldimine 9 (14.5 g, 77.3 mmol)
and N-methylimidazole (12.3 mL, 155 mmol) in 618 mL of
dichloromethane was treated with homophthalic anhydride (12.5 g,
77.3 mmol) in one portion. The solution was stirred for 16 h, and then
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The Journal of Organic Chemistry
Article
structures have little conformational flexibility of consequence, and only
one significant conformation of either structure was located, in which
the ring pucker places the pyridyl substituent pseudoequatorial. The
remaining rings were essentially perfectly planar. Rotation about the
C4−CO2H and C3−pyridyl was deemed unlikely to make a significant
difference either for the energy or for the computed NMR properties of
the C-3 and C-4 protons, and so was not explored. The major
(2S,3S,4R) diastereomer was calculated to lie 3.3 kcal/mol lower in free
energy than the minor (2R,3S,4R) diastereomer at 298 K.
Proton NMR properties were computed according to the procedures
recommended by Bally and Rablen and co-worker.18,19 Chemical shifts
were computed by using GIAO/WP04/cc-pVDZ and a simulated
chloroform solvent (SCRF). Magnetic shielding values were converted
into chemical shift values according to the equation d = (31.8440 − S))/
1.0205, where S is the magnetic shielding and d the chemical shift.
Coupling constants were computed in the gas phase at B3LYP/6-
31G(d,p)u+1s and scaled by 0.916.20,21
(10) Guibe-Jampel, E.; Bram, G.; Vilkas, M. Bull. Soc. Chim. Fr. 1973,
1021−1027.
(11) Hofle, G.; Steglich, W.; Vorbruggen, H. Angew. Chem., Int. Ed.
̈
̈
Engl. 1978, 17, 569−583.
(12) Scriven, E. F. V. Chem. Soc. Rev. 1983, 12, 129−161.
(13) Acyl cation affinity calculations: Lindner, C.; Tandon, R.;
Maryasin, B.; Larionov, E.; Zipse, H. Beilstein J. Org. Chem. 2012, 8,
1406−1442.
(14) Yu, N.; Bourel, L.; Deprez, B.; Gesquiere, J.-C. Tetrahedron Lett.
1998, 39, 829−832.
(15) Haimova, M. A.; Mollov, N. M.; Ivanova, S. C.; Dimitrova, A. I.;
Ognyanov, V. I. Tetrahedron 1977, 33, 331−336.
(16) Taydakov, I. V.; Krasnoselskiy, S. S.; Dutova, T. Y. Synth.
Commun. 2011, 41, 2430−2434.
(17) Frisch, M. J.; et al. Gaussian 09, Revision A.02; Gaussian, Inc.:
Wallingford, CT, 2009. The full reference is provided in the Supporting
Information.
(18) Jain, R.; Bally, T.; Rablen, P. R. J. Org. Chem. 2009, 74, 4017−
4023.
ASSOCIATED CONTENT
■
(19) Bally, T.; Rablen, P. R. J. Org. Chem. 2011, 76, 4818−4830.
(20) Deng, W.; Cheeseman, J. R.; Frisch, M. J. J. Chem. Theory Comput.
2006, 2, 1028−1037.
(21) Lutnæs, O. B.; Ruden, T. A.; Helgaker, T. Magn. Reson. Chem.
2004, 42, S117−127.
S
* Supporting Information
1H and 13C NMR spectra of new compounds; calculated
coordinates, chemical shifts, and coupling constants; and
crystallographic details and CIF’s for (−)-10 (CCDC
1007451) and 15 (CCDC 1007452). This material is available
free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: spencer.knapp@rutgers.edu.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful to the NIH (AI090662) and Medicines for
Malaria Venture for financial support, the Rutgers Aresty
Foundation for an undergraduate fellowship for A.L., and
Freeslate (Sunnyvale, CA) for assistance with the resolution.
Computational resources to support this work were provided by
the chemistry departments of Swarthmore College and the
University of Fribourg, Switzerland.
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