Concise synthesis of the isothiourea organocatalysts homobenzotetramisole and derivatives

Article abstract of DOI:10.1021/jo400603n

A concise approach to the synthesis of homobenzotetramisole and derivatives is described. Our strategy features a one-pot acylation-cyclization of 2-aminobenzothiazole with α,β-unsaturated acid chlorides to afford annulated pyrimidones. Subsequent Grignard addition followed by acid-promoted dehydration and reduction provides good overall yields of the title compounds in three steps and in quantities up to 10 g. The synthesis employs low-cost and readily available starting materials and enables access to both optical antipodes of these increasingly useful nucleophilic catalysts following chiral separation.

Full text of DOI:10.1021/jo400603n

Note
pubs.acs.org/joc
Concise Synthesis of the Isothiourea Organocatalysts
Homobenzotetramisole and Derivatives
Beatrice Ranieri,†,∇ Omar Robles,∇ and Daniel Romo*
Department of Chemistry, Texas A&M University, P.O. Box 30012, College Station, Texas 77842-3012, United States
S
* Supporting Information
ABSTRACT: A concise approach to the synthesis of homobenzotetramisole
and derivatives is described. Our strategy features a one-pot acylation−
cyclization of 2-aminobenzothiazole with α,β-unsaturated acid chlorides to
afford annulated pyrimidones. Subsequent Grignard addition followed by acid-
promoted dehydration and reduction provides good overall yields of the title
compounds in three steps and in quantities up to 10 g. The synthesis employs
low-cost and readily available starting materials and enables access to both
optical antipodes of these increasingly useful nucleophilic catalysts following
chiral separation.
ver the past decade, homobenzotetramisole (HBTM)
and related amidine and isothiourea-based organo-
HBTM in serviceable yields (Scheme 1). A shortcoming of this
synthesis is the cost of the enantiomeric β-amino alcohol 8, and
O
catalysts 1−6 have emerged as powerful tools for asymmetric
organocatalysis (Figure 1).1 These Lewis bases are capable of
Scheme 1. Synthetic Strategies to HBTM and Derivatives
Figure 1. Amidine and isothiourea-based acyl transfer catalysts.
while a synthesis of these amino alcohols is available involving a
resolution, the synthesis requires five steps and does not readily
lend itself to access HBTM derivatives. Reported routes to
substituted derivatives of HBTM also involve multistep
syntheses of the requisite β-amino alcohols.2f
We envisioned that HBTM (4a) and derivatives (e.g., 5, 6)
could be accessed in a convergent manner through addition of
organometallic reagents to 4-dihydropyrimidones 9 followed by
dehydration and reduction of the resulting hemiaminals. The
required 4-dihydropyrimidones 9 could be accessed by a one-
pot bis-cyclization of 2-aminobenzothiazole (10) with a variety
of α,β-unsaturated acid chlorides or related synthons (Scheme
promoting a number of asymmetric transformations including
kinetic resolution of alcohols,2 dynamic kinetic resolution of
azlactones,3 kinetic resolution of β-lactams,4 nucleophile-
catalyzed aldol lactonization (NCAL) processes,5 asymmetric
intra- and intermolecular Michael addition lactonizations,6 and
asymmetric α-amination of carboxylic acids,7 among others.8
Furthermore, HBTM and derivatives have found utility for the
determination of the absolute configuration of secondary
alcohols, lactams, and oxazolidinones due to the large
differential reaction rates observed during kinetic resolution
with these catalysts.9
HBTM (4a) was first reported by Birman and co-workers in
2008.2c The synthetic approach involved an aromatic
substitution of 2-chlorobenzothiazole 7 with the optically
active β-amino alcohol 8 followed by cyclization to provide
Received: March 22, 2013
© XXXX American Chemical Society
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1). Herein we describe the implementation of this concise
strategy to HBTM and derivatives that is easily scalable and
utilizes inexpensive, commercially available materials.
Table 1. Scope of the One-Pot Cyclization
We first sought reaction conditions to promote the bis-
cyclization of 2-aminobenzothiazole with α,β-unsaturated acid
chlorides or β-chloro acid chlorides with 2-aminobenzothiazole
to provide the desired 4-dihydropyrimidone 9a in a single
reaction vessel. In our initial studies, we treated 2-amino-
benzothiazole with 3-chloropropanoyl chloride (12) in
acetonitrile with catalytic dimethylaminopyridine (DMAP) at
0 °C which initially provided the corresponding N-acylated
product. Subsequent heating to reflux following addition of
solid Na2CO3 afforded the desired 4-dihydropyrimidone 9a in
54% yield (Scheme 2). We then sought to explore the potential
Scheme 2. Initial Routes to the Pyrimidone 9a via a Single-
Pot, Bis-Cyclization
a
b
Values refer to isolated yields. Ratios were determined by analysis of
1
the crude reaction mixture by H NMR (500 MHz).
use of α,β-unsaturated acid chlorides, given their greater
availability, lower cost, and the possibility that in situ β-
elimination was occurring to give the same intermediate 13
from chloride 12. In the case of acryloyl chloride, identical
reaction conditions also provided the desired pyrimidone 9a in
an improved 67% yield (Scheme 2). However, when we
attempted to apply these reaction conditions to other
unsaturated acid chlorides, low yields were obtained. This
prompted us to optimize this cyclization process for other
unsaturated acid chlorides.
After some experimentation, we found that use of NaI, as an
additive (1.0 equiv), dramatically improved the overall yields of
the bis-cyclization. Initial N-acylation of 2-aminobenzothiazole
with acryloyl chloride could be achieved with Na2CO3 in
acetonitrile at 0 °C and provided the corresponding acylated
product in nearly quantitative yields. Heating the initial acylated
adduct 13 to reflux in the presence of NaI afforded the desired
dihydropyrimidone 9a in 86% yield (Table 1, entry 1). Based
on our hypothesis that the iodide ion was promoting the
cyclization step through a transient alkyl iodide, formed by
conjugate addition of iodide to the unsaturated amide, and
subsequent intramolecular SN2 reaction, we briefly explored
other additives. These included DMAP and imidazole;
however, NaI provided the best yields.10 Substituted α,β-
unsaturated acid chlorides were also good substrates for this
reaction. Methacryloyl chloride and crotonyl chloride provided
the substituted dihydropyrimidones 9b and 9c in serviceable
yields (entries 2 and 3, respectively). Cinnamoyl chloride,
however, afforded only low yields of the desired cyclized
product 9d (entry 4). The bis-substituted acid chloride 11e also
provided a low yield of the cycloadduct 9e (entry 5). In these
latter examples, a major byproduct isolated was the N-acylated
intermediate (cf. 13) that had not undergone cyclization.
With dihydropyrimidones 9 in hand, we next explored the
planned Grignard addition−dehydration−reduction sequence.
Following optimization, monoaddition of phenyl Grignard to
dihydropyrimidone 9a was achieved at −15 °C in THF to
deliver hemiaminal 14. Dehydration in situ gave the
corresponding enamines 15 by careful quenching with TFA.
This acid-promoted dehydration also facilitated isolation of the
products by simple extraction of the corresponding enamines,
enabling direct reduction without the need for further
purification. Reduction to the isothiourea was readily achieved
by treatment of the enamine intermediates with Et3SiH in TFA
at −15 °C. In this manner, HBTM (4a) was obtained in 71%
on 1 g scale and was reliably scaled up to 10 g scale in
comparable yield (68%, Table 2, entry 1).
We explored the scope of this sequence with other Grignard
reagents. Both electron-deficient and -rich p-substituted phenyl
Grignard reagents provided the corresponding HBTM
derivatives 4b−c in good yields (entries 2−3). 3-Methyl-
thiophen-2-yl magnesium bromide also afforded the expected
thiophene HBTM derivative 4d in modest yield (entry 4).
The use of 2-naphthyl and 9-phenanthryl Grignard reagents
gave access to HBTM derivatives 4e−f bearing bulkier
substituents in moderate yields (entries 5−6). This trans-
formation was then extended to substituted dihydropyrimi-
dones 9b and 9c with phenyl magnesium bromide to provide
bis-substituted HBTM congeners 5 and 4g in modest yields but
good diastereoselectivities (entries 7−8).11
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Table 2. Scope of the Grignard Addition/Reduction Sequence
a
b
c
d
Values refer to isolated yields. Reaction performed on a 1 g scale. Reaction performed on a 10 g scale. The reduction was performed at −40 °C.
1
Diastereomeric ratios (dr) were determined by analysis of crude reaction mixtures by H NMR (500 MHz).
The described synthetic approach provides practical access to
racemic HBTM and derivatives in a highly concise manner.
Importantly, enantiomer separation would enable facile access
to both optical antipodes of HBTM. This was accomplished on
preparative scale (a 5 g batch) using supercritical fluid
chromatography (SFC), providing both (R)-HBTM (2.4 g,
>99% ee) and (S)-HBTM (2.3 g, >99% ee) in high optical
purity and mass recovery.12
In summary, we developed a concise and convenient
approach for the synthesis of racemic HBTM and derivatives.
Our strategy features a single-pot acylation−cyclization of 2-
aminobenzothiazole with α,β-unsaturated acid chlorides to
afford the corresponding dihydropyrimidones. Subsequent
Grignard addition followed by dehydration and reduction of
the corresponding enamines provides the desired isothioureas
in three steps from commercially available reagents. The
described approach is scalable as demonstrated for the synthesis
of up to 10 g of racemic HBTM and uses low-cost and readily
available starting materials. The strategy will enable access to
both optical antipodes of HBTM and derivatives on scale and
should facilitate access to these increasingly useful chiral,
nucleophilic organocatalysts.
EXPERIMENTAL SECTION
■
General Procedures. All reactions were carried out under a
nitrogen atmosphere in oven-dried or flame-dried glassware using dry
solvents under anhydrous conditions. All anhydrous solvents were
dried with activated molecular sieves (3 Å or 4 Å beads) and tested for
trace water content with a coulometric Karl Fischer titrator. All
solvents used for extraction and chromatography procedures were
used as received from commercial suppliers without further
purification. All reagents were purchased and used as received unless
otherwise noted. 1H and 13C NMR spectra were measured in
deuterated chloroform (CDCl3) at 500 MHz/125 MHz, respectively.
All proton NMR spectra were recorded at 500 MHz and were
referenced with residual chloroform (7.27 ppm) and reported in parts
per million (ppm). Coupling constants (J) are reported in hertz (Hz).
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Abbreviations for signal coupling are as follows: s, singlet; d, doublet; t,
triplet; q, quartet; p, pentet; dd, doublet of doublets; ddd, doublet of
doublet of doublets; dt, doublet of triplets; dq, doublet of quartets; m,
multiplet; bs, broad singlet. All carbon NMR spectra were measured at
125 MHz and were referenced with residual chloroform (77.23 ppm)
and reported in parts per million (ppm). All FT-IR spectra were
recorded on sodium chloride discs. High-resolution mass spectra (ESI
or MALDI) were obtained using a quadruple time-of-flight mass
spectrometer (QTOF). Analytical thin layer chromatography (TLC)
was performed on precoated glass backed plates (silica gel 60F254; 0.25
mm thickness). Flash chromatography was carried out with silica gel
60 Å (230−400 mesh ASTM) and basic alumina 60 Å (50−200 μm).
Representative Procedure for the One-Pot Cyclization. The
2-aminobenzothiazole (1.0 equiv, 0.5−10 g) and Na2CO3 (2.2 equiv)
were suspended in dry acetonitrile, and then the suspension was
cooled to 0 °C. The corresponding acid chloride (1.2 equiv) was then
added dropwise, and the resulting reaction mixture was stirred at 0 °C
for 2 h. NaI (1.0 equiv) was then added, and the reaction mixture was
heated to 80 °C with stirring until TLC analysis indicated completion
of the reaction (8−48 h). The reaction was concentrated under
reduced pressure, diluted with water, and extracted with dichloro-
methane (3×). The combined organic fractions were dried over
MgSO4, filtered, and concentrated under reduced pressure, and the
crude was purified by MPLC on silica gel using a gradient of
dichloromethane and acetone as eluent.
3,4-Dihydro-2H-benzo[4,5]thiazolo[3,2-a]pyrimidin-2-one
(9a). Dihydropyrimidone 9a was prepared according to the
representative procedure from 2-aminobenzothiazole (1.0 g, 6.66
mmol), Na2CO3 (1.55 g, 14.65 mmol) in acetonitrile (40 mL) and
acryloyl chloride (0.646 mL, 7.99 mmol), and NaI (0.998 g, 6.66
mmol) after a reaction time of 8 h. Purification was performed by
MPLC on silica gel using a gradient of dichloromethane and acetone
(9:1 → 1:1) as eluent to afford the desired product (1.165 g, 86%) as a
light yellow solid. 1H NMR (500 MHz, CDCl3) δ 7.57 (dd, J = 8.0, 1.0
Hz 1H), 7.44 (ddd, J = 8.0, 8.0, 1.0 Hz, 1H), 7.27 (ddd, J = 8.0, 8.0, 1.0
Hz, 1H), 7.16 (d, J = 8.0 Hz, 1H), 4.23 (t, J = 7.5, 2H), 2.86 (t, J = 7.0
Hz, 2H). 13C NMR (125 MHz, CDCl3) δ 173.66, 173.20, 138.43,
127.40, 124.33, 123.43, 122.81, 110.81, 41.12, 28.44. FT-IR (neat,
cm−1): 1655, 1509, 1471, 1369. HRMS (ESI+): Calcd for C10H9N2OS
([M+H]+), 205.0436. Found: 205.0441.
8.0, 7.0, 0.5 Hz, 1H), 7.18 (d, J = 8.0 Hz, 1H), 4.72 (p, J = 7.0 Hz,
1H), 3.01 (dd, J = 16.0, 7.0 Hz, 1H), 2.66 (d, J = 16.0 Hz, 1H), 1.43
(d, J = 7.0 Hz, 3H). 13C NMR (125 MHz, CDCl3) δ 173.46, 171.97,
137.64, 127.45, 124.28, 123.94, 123.04, 110.74, 48.83, 35.58, 17.97.
FT-IR (neat, cm−1): 2976, 1671, 1505, 1468, 1360. HRMS (ESI+):
Calcd for C11H11N2OS ([M+H]+), 219.0592. Found: 219.0584.
(
)-4-Phenyl-3,4-dihydro-2H-benzo[4,5]thiazolo[3,2-a]-
pyrimidin-2-one (9d). Dihydropyrimidone 9d was prepared
according to the representative procedure from 2-aminobenzothiazole
(1.0 g, 6.66 mmol), Na2CO3 (1.55 g, 14.65 mmol) in acetonitrile (40
mL) and cinnamoyl chloride (1.33 mL, 7.99 mmol), and NaI (0.998 g,
6.66 mmol) after a reaction time of 48 h. Purification was performed
by MPLC on silica gel using a gradient of dichloromethane and
acetone (9:1 → 1:1) as eluent to afford the desired product (0.190 g,
10%) as a light orange solid. 1H NMR (500 MHz, CDCl3) δ 7.58 (dd,
J = 8.0, 1.0 Hz 1H), 7.33−7.28 (m, 5H), 7.23 (ddd, J = 8.0, 8.0, 1.0 Hz,
1H), 7.17 (dd, J = 8.0, 1.0 Hz, 1H), 6.99 (d, J = 8.0 Hz, 1H), 5.62 (d, J
= 8.0 Hz, 1H), 3.29 (dd, J = 16.0, 8.0 Hz, 1H), 2.91 (dd, J = 16.0, 1.5
Hz, 1H). 13C NMR (125 MHz, CDCl3) δ 173.21, 172.49, 138.05,
137.20, 129.72, 129.10, 127.43, 125.55, 124.47, 123.52, 122.87, 111.56,
56.37, 36.98. FT-IR (neat, cm−1): 3043, 1668, 1537, 1467, 1362.
HRMS (ESI+): Calcd for C16H13N2OS ([M+H]+), 281.0749. Found:
281.0738.
(
)-4-Methyl-3,4-dihydro-2H-benzo[4,5]thiazolo[3,2-a]-
pyrimidin-2-one (9e). Dihydropyrimidone 9e was prepared
according to the representative procedure from 2-aminobenzothiazole
(0.5 g, 3.33 mmol), Na2CO3 (0.776 g, 7.32 mmol) in acetonitrile (20
mL) and tigloyl chloride (0.439 mL, 3.99 mmol), and NaI (0.499 g,
3.33 mmol) after a reaction time of 36 h. Purification was performed
by MPLC on silica gel using a gradient of dichloromethane and
acetone (9:1 → 1:1) as eluent to afford the desired product (0.149 g,
19%, 5:1 dr) as a light orange solid. Data for the major diastereomer
1
(anti) 9e: H NMR (500 MHz, CDCl3) δ 7.56 (d, J = 8.0 Hz 1H),
7.43 (ddd, J = 8.0, 8.0, 1.0 Hz, 1H), 7.25 (ddd, J = 8.0, 8.0, 1.0 Hz,
1H), 7.15 (d, J = 8.0 Hz, 1H), 4.72 (p, J = 7.0 Hz, 1H), 3.03 (p, J = 7.0
Hz, 1H), 1.30 (d, J = 7.0 Hz, 3H), 1.26 (d, J = 7.0 Hz, 3H). 13C NMR
(125 MHz, CDCl3) δ 176.66, 171.28, 137.61, 127.34, 124.10, 124.06,
122.99, 110.61, 53.43, 37.43, 12.47, 11.28. FT-IR (neat, cm−1): 2929,
1681, 1504, 1468, 1360. HRMS (ESI+): Calcd for C12H13N2OS ([M
+H]+), 233.0749. Found: 233.0756.
1
Data for the minor diastereomer (cis) 9e′: H NMR (500 MHz,
This reaction was also carried out on 10 g scale (2-amino-
benzothiazole), and the product was recrystallized from ethanol (two
crops from 550 and 250 mL sequentially) to give the desired product
(11.4 g, 84%) without further purification.
CDCl3) δ 7.60 (dd, J = 8.0, 1.0 Hz 1H), 7.46 (ddd, J = 8.0, 8.0, 1.0 Hz,
1H), 7.29 (ddd, J = 8.5, 8.0, 1.0 Hz, 1H), 7.17 (d, J = 8.5 Hz, 1H), 4.30
(q, J = 7.0 Hz, 1H), 2.71 (q, J = 7.0 Hz, 1H), 1.42 (d, J = 7.0 Hz, 3H),
1.31 (d, J = 7.0 Hz, 3H). 13C NMR (125 MHz, CDCl3) δ 177.98,
170.73, 138.21, 127.45, 124.32, 124.26, 123.13, 110.59, 55.51, 40.81,
18.14, 17.44. FT-IR (neat, cm−1): 2930, 1681, 1504, 1468, 1360.
HRMS (ESI+): Calcd for C12H13N2OS ([M+H]+), 233.0749. Found:
233.0754.
(
)-3-Methyl-3,4-dihydro-2H-benzo[4,5]thiazolo[3,2-a]-
pyrimidin-2-one (9b). Dihydropyrimidone 9b was prepared
according to the representative procedure from 2-amino-benzothiazole
(1.0 g, 6.66 mmol), Na2CO3 (1.55 g, 14.65 mmol) in acetonitrile (40
mL) and methacryloyl chloride (0.773 mL, 7.99 mmol), and NaI
(0.998 g, 6.66 mmol) after a reaction time of 24 h. Purification was
performed by MPLC on silica gel using a gradient of dichloromethane
and acetone (9:1 → 1:1) as eluent to afford the desired product (1.010
Representative Procedure for the Grignard Addition−
Dehydration−Reduction Sequence As Described for
( )-HBTM. The corresponding pyrimidin-2-one (1.0 equiv, 0.5−10
g) was suspended in dry THF and then cooled −15 °C. The
corresponding Grignard reagent (1.2 equiv) was then added dropwise,
and the reaction mixture was stirred at −15 °C for 5 h. Trifluoroacetic
acid (3.0 equiv) was then carefully added, and the reaction was stirred
at −15 °C for 30 min. The mixture was concentrated under reduced
pressure, diluted with water, and extracted with EtOAc (4×). The
combined organic layers were dried over MgSO4, filtered, and
concentrated under reduced pressure. Et3SiH was added (15 equiv)
to the crude mixture, and the mixture was cooled to −15 °C.
Trifluoroacetic acid was added, and the reaction was stirred vigorously
at −15 °C for 6 h. The reaction was then concentrated under reduced
pressure, washed with hexanes (3×), diluted with EtOAc, and washed
with NaOH 1.5 M (3×, pH of the aqueous phases was 10−11). The
combined aqueous fractions were extracted with EtOAc (4×), and the
combined organic fractions were dried over MgSO4, filtered, and
concentrated under reduced pressure. The crude residue was purified
by aluminum oxide flash chromatography using hexanes and ethyl
acetate as eluent.
1
g, 70%) as a light yellow solid. H NMR (500 MHz, CDCl3) δ 7.58
(dd, J = 8.0, 1.0 Hz 1H), 7.45 (ddd, J = 8.5, 8.0, 1.0 Hz, 1H), 7.28
(ddd, J = 8.5, 8.0, 1.0 Hz, 1H), 7.16 (d, J = 8.0 Hz, 1H), 4.32 (dd, J =
12.0, 7.0 Hz, 1H), 3.76 (t, J = 12.0 Hz, 1H), 2.92−2.84 (m, 1H), 1.38
(d, J = 6.5 Hz, 3H). 13C NMR (125 MHz, CDCl3) δ 177.03, 172.46,
138.54, 127.40, 124.32, 123.68, 122.94, 110.72, 47.33, 32.62, 14.03.
FT-IR (neat, cm−1): 2930, 1673, 1504, 1470, 1368. HRMS (ESI+):
Calcd for C11H11N2OS ([M+H]+), 219.0592. Found: 219.0588.
(
)-4-Methyl-3,4-dihydro-2H-benzo[4,5]thiazolo[3,2-a]-
pyrimidin-2-one (9c). Dihydropyrimidone 9c was prepared
according to the representative procedure from 2-aminobenzothiazole
(1.0 g, 6.66 mmol), Na2CO3 (1.55 g, 14.65 mmol) in acetonitrile (40
mL) and crotonoyl chloride (0.765 mL, 7.99 mmol), and NaI (0.998 g,
6.66 mmol) after a reaction time of 36 h. Purification was performed
by MPLC on silica gel using a gradient of dichloromethane and
acetone (9:1 → 1:1) as eluent to afford the desired product (0.896 g,
62%) as a light orange solid. 1H NMR (500 MHz, CDCl3) δ 7.58 (dd,
J = 8.0, 0.5 Hz 1H), 7.45 (ddd, J = 8.0, 7.0, 0.5 Hz, 1H), 7.27 (ddd, J =
D
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Note
(
)-2-Phenyl-3,4-dihydro-2H-benzo[4,5]thiazolo[3,2-a]-
−15 °C for 6 h. The crude residue was purified by flash
chromatography on aluminum oxide using hexanes/ethyl acetate
(8:2) as eluent to provide compound 4d as a light brown viscous oil
pyrimidine, HBTM (4a). HBTM (4a) was prepared according to the
representative procedure from pyrimidin-2-one 9a (1.0 g, 4.90 mmol)
in THF (50 mL) and PhMgBr (5.88 mL, 1.0 M in THF, 5.88 mmol)
at −15 °C for 5 h and then quenched with trifluoroacetic acid (1.11
mL, 14.70 mmol) at −15 °C for 30 min. The reduction step was
carried out with Et3SiH (12 mL, 73.50 mmol) and trifluoroacetic acid
(50 mL) at −15 °C for 6 h. The crude residue was purified by flash
chromatography on aluminum oxide using hexanes and ethyl acetate
(95:5 → 60:40) as eluent to provide ( )-HBTM (4a) as an off-white
solid (0.931 g, 71%). All spectroscopic and physical data for this
compound were identical to data reported by Birman.2c 1H NMR (500
MHz, CDCl3) δ 7.36−7.32 (m, 5H), 7.28−7.25 (m, 1H), 7.21 (ddd, J
= 8.0, 8.0, 1.0 Hz, 1H), 7.02 (ddd, J = 8.0, 7.5, 1.0 Hz, 1H), 6.76 (d, J =
7.5 Hz, 1H), 4.74 (dd, J = 8.0, 4.0 Hz, 1H), 3.86−3.81 (m, 1H), 3.72−
3.68 (m, 1H), 2.35−2.29 (m, 1H), 2.04−1.97 (m, 1H). HRMS (ESI
+): Calcd for C16H15N2S ([M+H]+), 267.0956. Found: 267.0952.
This reaction was also performed on 10 g scale (10 g of pyrimidin-
2-one, 9a), and the product was purified by filtration on an aluminum
oxide plug using hexanes and ethyl acetate (95:5 → 60:40) as eluent to
provide ( )-HBTM (4a) as an off-white solid (8.75 g, 68%).
Separation of 5 g of HBTM was accomplished by Lotus Separations,
Ltd. by supercritical fluid chromatography to provide 2.4 g of the R
enantiomer (>99% ee) and 2.3 g of the S enantiomer (>99% ee).
( )-2-(4-Chlorophenyl)-3,4-dihydro-2H-benzo[4,5]thiazolo-
[3,2-a]pyrimidine (4b). Compound 4b was prepared according to
the representative procedure from pyrimidin-2-one 9a (0.5100 g, 2.50
mmol) in THF (50 mL) and 4-Cl-PhMgBr (3.7 mL, 1.0 M in THF,
3.70 mmol) at −15 °C for 5 h and then quenched with trifluoroacetic
acid (0.6 mL, 7.50 mmol) at −15 °C for 30 min. The reduction step
was carried out with Et3SiH (6 mL, 37.4 mmol) and trifluoroacetic
acid (50 mL) at −15 °C for 6 h. The crude residue was purified by
flash chromatography on aluminum oxide using hexanes and ethyl
acetate (8:2 → 1:1) as eluent to provide compound 4b as a light
yellow solid (0.457 g, 60%). 1H NMR (500 MHz, CDCl3) δ 7.34−7.29
(m, 5H), 7.22 (ddd, J = 7.5, 7.5, 1.0 1H), 7.03 (ddd, J = 8.0, 7.5, 1.0
Hz, 1H), 6.76 (d, J = 8.0 Hz, 1H), 4.69 (dd, J = 8.5, 4.0 Hz, 1H),
3.86−3.80 (m, 1H), 3.73−3.69 (m, 1H), 2.33−2.27 (m, 1H), 1.97−
1.89 (m, 1H). 13C NMR (125 MHz, CDCl3) δ 158.31, 142.93, 140.56,
132.46, 128.52, 128.07, 125.96, 122.36, 121.86, 107.58, 57.83, 40.61,
27.92. FT-IR (neat, cm−1): 2959, 2922, 2881, 1632, 1582. HRMS (ESI
+): Calcd for C16H14ClN2S ([M+H]+), 301.0566. Found: 301.0561.
1
(90 mg, 32%). H NMR (500 MHz, CDCl3) δ 7.32 (d, J = 7.5, 1H),
7.21 (ddd, J = 8.0, 7.5, 1.0 Hz, 1H), 7.10 (d, J = 5.0 Hz, 1H), 7.03
(ddd, J = 7.5, 7.5, 1.0 Hz, 1H), 6.82 (d, J = 5.0 Hz, 1H), 6.78 (d, J =
8.0 Hz, 1H), 4.98 (dd, J = 8.0, 4.0 Hz, 1H), 3.87−3.78 (m, 2H), 2.34−
2.29 (m, 1H), 2.26 (s, 3H), 2.06−1.99 (m, 1H). 13C NMR (125 MHz,
CDCl3) δ 158.99, 141.61, 140.50, 131.91, 130.37, 126.12, 122.70,
122.59, 122.22, 122.05, 107.91, 53.12, 40.68, 26.89, 14.00. FT-IR
(neat, cm−1): 1619. HRMS (ESI+): Calcd for C15H15N2S2 ([M+H]+),
287.0677. Found: 287.0668.
( )-2-(Naphthalen-2-yl)-3,4-dihydro-2H-benzo[4,5]thiazolo-
[3,2-a]pyrimidine (4e). Compound 4e was prepared according to
the representative procedure from pyrimidin-2-one 9a (0.5 g, 2.40
mmol) in THF (50 mL) and 2-naphthylmagnesium bromide (14.7
mL, 0.25 M in Me-THF, 3.7 mmol) at −15 °C for 5 h and then
quenched with trifluoroacetic acid (0.6 mL, 7.50 mmol) at −15 °C for
30 min. The reduction step was carried out with Et3SiH (5.9 mL, 36.70
mmol) and trifluoroacetic acid (50 mL) at −15 °C for 6 h. The crude
residue was purified by flash chromatography on aluminum oxide
using hexanes and ethyl acetate (95:5 → 60:40) as eluent to provide
1
compound 4e as a light yellow solid (0.400 g, 50%). H NMR (500
MHz, CDCl3) δ 7.86−7.83 (m, 4H), 7.49−7.44 (m, 3H), 7.36 (d, J =
8.0 Hz, 1H), 7.22 (ddd, J = 8.0, 8.0, 1.0 Hz, 1H), 7.04 (ddd, J = 8.0,
8.0, 1.0 Hz, 1H), 6.76 (d, J = 8.0 Hz, 1H), 4.90 (dd, J = 8.0, 4.0 Hz,
1H), 3.87−3.82 (m, 1H), 3.72−3.67 (m, 1H), 2.41−2.35 (m, 1H),
2.10−204 (m, 1H). 13C NMR (125 MHz, CDCl3) δ 158.42, 141.71,
140.78, 133.58, 132.73, 128.31, 128.10, 127.72, 126.08, 126.01, 125.65,
125.28, 125.16, 122.64, 121.98, 121.90, 107.63, 58.56, 40.62, 27.91.
FT-IR (neat, cm−1): 3055, 2956, 2925, 2872, 1619, 1588. HRMS (ESI
+): Calcd for C20H17N2S ([M+H]+), 317.1112. Found: 317.1106.
(
)-2-(Phenanthren-9-yl)-3,4-dihydro-2H-benzo[4,5]-
thiazolo[3,2-a]pyrimidine (4f). Compound 4f was prepared
according to the representative procedure from pyrimidin-2-one 9a
(400 mg, 2.00 mmol) in THF (50 mL) and 9-phenanthrenylmagne-
sium bromide (5.9 mL, 0.5 M in THF, 2.9 mmol) at −15 °C for 5 h
and then quenched with trifluoroacetic acid (0.6 mL, 7.50 mmol) at
−15 °C for 30 min. The reduction step was carried out with Et3SiH
(4.7 mL, 29.4 mmol) and trifluoroacetic acid (50 mL) at −15 °C for 6
h. The crude residue was purified by flash chromatography on
aluminum oxide using hexanes/ethyl acetate (8:2) as eluent to provide
1
compound 4f as a light orange solid (118 mg, 40%). H NMR (500
(
)-2-(4-Methoxyphenyl)-3,4-dihydro-2H-benzo[4,5]-
thiazolo[3,2-a]pyrimidine (4c). Compound 4c was prepared
according to the representative procedure from pyrimidin-2-one 9a
(55 mg, 0.27 mmol) in THF (5 mL) and 4-MeO-PhMgBr (808 μL,
0.5 M in THF, 0.404 mmol) at −15 °C for 5 h and then quenched
with trifluoroacetic acid (0.6 mL, 7.50 mmol) at −15 °C for 30 min.
The reduction step was carried out with Et3SiH (652 μL, 4.0 mmol)
and trifluoroacetic acid (5 mL) at −15 °C for 6 h. The crude residue
was purified by flash chromatography on aluminum oxide using
hexanes and ethyl acetate (7:3 → 1:1) as eluent to provide compound
4c as a light yellow solid (40 mg, 51%). 1H NMR (500 MHz, CDCl3)
δ 7.32 (dd, J = 7.5, 1.0, 1H), 7.27 (d, J = 8.5 Hz, 2H), 7.21 (ddd, J =
8.0, 7.5, 1.0 Hz, 1H), 7.02 (ddd, J = 8.0, 7.5, 1.0 Hz, 1H), 6.89 (d, J =
8.5 Hz, 2H), 6.75 (d, J = 7.5 Hz, 1H), 4.69 (dd, J = 8.0, 4.0 Hz, 1H),
3.84−3.79 (m, 1H), 3.80 (s, 3H), 3.71−3.66 (m, 1H), 2.31−2.25 (m,
1H), 2.00−1.93 (m, 1H). 13C NMR (125 MHz, CDCl3) δ 158.63,
158.03, 140.84, 136.56, 127.75, 125.96, 122.65, 121.94, 121.81, 113.93,
107.53, 57.98, 55.44, 40.60, 28.03. FT-IR (neat, cm−1): 2956, 2925,
1626, 1581. HRMS (ESI+): Calcd for C17H17N2OS ([M+H]+),
297.1062. Found: 297.1065.
MHz, CDCl3) δ 8.79 (dd, J = 7.5, 2.0 Hz, 1H), 8.67 (d, J = 8.0 Hz,
1H), 8.11 (dd, J = 7.5, 2.0 Hz, 1H), 7.90 (dd, J = 7.5, 1.0 Hz, 1H), 7.83
(s, 1H), 7.69 (ddd, J = 8.0, 8.0, 1.5 Hz, 1H), 7.67 (ddd, J = 8.0, 8.0, 1.5
Hz, 1H), 7.63 (ddd, J = 8.0, 8.0, 1.5 Hz, 1H), 7.58 (ddd, J = 8.0, 8.0,
1.0 Hz, 1H), 7.38 (dd, J = 8.0, 1.0 1H), 7.21 (ddd, J = 8.0, 8.0, 1.0 1H),
7.05 (ddd, J = 8.0, 8.0, 1.0 Hz, 1H), 6.72 (d, J = 8.0 Hz, 1H), 5.52 (dd,
J = 8.0, 4.0 Hz, 1H), 3.84−3.79 (m, 1H), 3.61−3.57 (m, 1H), 2.53−
2.47 (m, 1H), 2.12−2.05 (m, 1H). 13C NMR (125 MHz, CDCl3) δ
158.73, 140.81, 137.31, 131.79, 131.14, 129.98, 129.88, 129.08, 126.81,
126.79, 126.54, 126.27, 126.05, 125.50, 123.70, 123.56, 122.74, 122.48,
122.02, 121.92, 107.66, 55.21, 40.51, 26.66. FT-IR (neat, cm−1): 3064,
2932, 2874, 1614, 1587. HRMS (ESI+): Calcd for C24H20N2S ([M
+H]+), 367.1269. Found: 367.1253.
( )-3-Methyl-2-phenyl-3,4-dihydro-2H-benzo[4,5]thiazolo-
[3,2-a]pyrimidine (5). Compound 5 was prepared according to the
representative procedure from pyrimidin-2-one 9b (200 mg, 0.916
mmol) in THF (10 mL) and PhMgBr (1.10 mL, 1.0 M in THF, 1.10
mmol) at −15 °C for 5 h and then quenched with trifluoroacetic acid
(0.5 mL, 7.35 mmol) at −15 °C for 30 min. The reduction step was
carried out with Et3SiH (2.4 mL, 14.69 mmol) and trifluoroacetic acid
(10 mL) at −40 °C and slowly warmed up to 0 °C for 6 h. The crude
residue was purified by flash chromatography on aluminum oxide
using hexanes and ethyl acetate (95:5 → 60:40) as eluent to provide
compound 5 as a light orange solid (0.106 g, 41%), as a single
diastereomer. All spectroscopic and physical data for this compound
matched those reported by Birman.2f 1H NMR (500 MHz, CDCl3) δ
7.38−7.19 (m, 7H), 6.94 (dd, J = 7.5, J = 7.5 Hz, 1H), 6.71 (d, J = 8.0
(
)-2-(3-Methylthiophen-2-yl)-3,4-dihydro-2H-benzo[4,5]-
thiazolo[3,2-a]pyrimidine (4d). Compound 4d was prepared
according to the representative procedure from pyrimidin-2-one 9a
(200 mg, 0.98 mmol) in THF (10 mL) and 3-methyl-2-
thienylmagnesium bromide (2.9 mL, 0.5 M in THF, 1.47 mmol) at
−15 °C for 5 h and then quenched with trifluoroacetic acid (0.6 mL,
7.50 mmol) at −15 °C for 30 min. The reduction step was carried out
with Et3SiH (2.4 mL, 14.69 mmol) and trifluoroacetic acid (10 mL) at
E
dx.doi.org/10.1021/jo400603n | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
Hz, 1H), 4.65 (d, J = 4.0 Hz, 1H), 3.76 (dd, J = 11.5, 4.5 Hz, 1H), 3.28
(dd, J = 11.5, 7.5 Hz, 1H), 2.37−2.30 (m, 1H), 0.73 (d, J = 7.0 Hz,
3H). HRMS (ESI+): Calcd for C17H17N2S ([M+H]+), 281.1112.
Found: 281.1106.
(3) Yang, X.; Lu, G.; Birman, V. B. Org. Lett. 2010, 12, 892.
(4) Bumbu, V. D.; Birman, V. B. J. Am. Chem. Soc. 2011, 133, 13902.
(5) (a) Purohit, V. C.; Matla, A. S.; Romo, D. J. Am. Chem. Soc. 2008,
130, 10478. (b) Leverett, C. A.; Purohit, V. C.; Romo, D. Angew.
Chem., Int. Ed. 2010, 49, 9479.
(6) Belmessieri, D.; Morrill, L. C.; Simal, C.; Slawin, A. M. Z.; Smith,
A. D. J. Am. Chem. Soc. 2011, 133, 2714.
(7) Morrill, L. C.; Lebl, T.; Slawin, A. M. Z.; Smith, A. D. Chem. Sci.
2012, 3, 2088.
(8) Yang, X.; Birman, V. B. Angew. Chem., Int. Ed. 2011, 50, 5553.
(9) (a) Wagner, A. J.; David, J. G.; Rychnovsky, S. D. Org. Lett. 2011,
13, 4470. (b) Perry, M. A.; Trinidad, J. V.; Rychnovsky, S. D. Org. Lett.
2013, 15, 472.
( )-3-Methyl-2-phenyl-3,4-dihydro-2H-benzo[4,5]thiazolo-
[3,2-a]pyrimidine (4g). Compound 4g was prepared according to
the representative procedure from pyrimidin-2-one 9c (200 mg, 0.916
mmol) in THF (10 mL) and PhMgBr (1.10 mL, 1.0 M in THF, 1.10
mmol) at −15 °C for 5 h and then quenched with trifluoroacetic acid
(0.5 mL, 7.35 mmol) at −15 °C for 30 min. The reduction step was
carried out with Et3SiH (2.4 mL, 14.69 mmol) and trifluoroacetic acid
(10 mL) at −40 °C and slowly warmed up to 0 °C for 6 h. The crude
residue was purified by flash chromatography on aluminum oxide
using hexanes and ethyl acetate (95:5 → 60:40) as eluent to provide
compound 4g as a light orange solid (0.112 g, 44%, 10:1 dr). All
spectroscopic and physical data for this compound matched those
reported by Birman.2f 1H NMR (500 MHz, CDCl3) δ 7.43−7.17 (m,
7H), 7.01 (dd, J = 13.0, J = 5.0 Hz, 1H), 6.83 (d, J = 8.0 Hz, 1H), 4.70
(dd, J = 8.0, 4.0 Hz, 1H), 4.33−4.28 (m, 1H), 2.06 (ddd, J = 13.0, 4.0,
1.5 Hz, 1H), 1.94 (ddd, J = 13.0, 12.0, 5.0 Hz, 1H), 1.56 (d, J = 6.5 Hz,
3H). HRMS (ESI+): Calcd for C17H17N2S ([M+H]+), 281.1112.
Found: 281.1118.
(10) Wakeham, R. J.; Taylor, J. E.; Bull, S. D.; Morris, J. A.; Williams,
J. M. J. Org. Lett. 2013, 15, 702.
(11) The use of bulky alkyl Grignard reagents which should provide
the highest facial selectivity during catalysis, e.g. isopropylmagnesium
bromide, was studied briefly; however no addition to the pyrimidine
was observed.
(12) SFC separations were performed by Lotus Separations LLC.
Further details of the preparative separation and analysis of the HBTM
enantiomers by chiral HPLC are provided in the Supporting
Information.
ASSOCIATED CONTENT
■
S
* Supporting Information
1H and 13C NMR spectra for all new compounds reported. This
material is available free of charge via the Internet at http://
pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: romo@tamu.edu.
■
Present Address
†Visiting student. Current address: Dipartimento Di Farmacia,
̀
Universita degli Studi di Parma, Parco Area Delle Scienze 27/A,
I-43124 Parma, Italy.
Author Contributions
∇These authors contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the National Science Foundation
(CHE-0809747) and the Robert A. Welch Foundation (A-
1280). B.R. acknowledges fellowship support from the
Ministero Italiano della Pubblica Istruzione for her stay in the
Romo lab.
REFERENCES
■
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