1,3,3-Trimethylindolin-5-amine and 4-Formylphenyl 4,4-Dimethylchroman-6-carboxylate Thiosemicarbazone (OHet72)

Full text of DOI:10.1080/00304948.2020.1834819

Organic Preparations and Procedures International
The New Journal for Organic Synthesis
ISSN: (Print) (Online) Journal homepage: https://www.tandfonline.com/loi/uopp20
1,3,3-Trimethylindolin-5-amine and 4-
Formylphenyl 4,4-Dimethylchroman-6-carboxylate
Thiosemicarbazone (OHet72)
Daniel J. Bryant , K. Darrell Berlin & Richard A. Bunce
To cite this article: Daniel J. Bryant , K. Darrell Berlin & Richard A. Bunce (2021) 1,3,3-
Trimethylindolin-5-amine and 4-Formylphenyl 4,4-Dimethylchroman-6-carboxylate
Thiosemicarbazone (OHet72), Organic Preparations and Procedures International, 53:1, 68-77,
DOI: 10.1080/00304948.2020.1834819
To link to this article: https://doi.org/10.1080/00304948.2020.1834819
Published online: 29 Dec 2020.
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ORGANIC PREPARATIONS AND PROCEDURES INTERNATIONAL
2021, VOL. 53, NO. 1, 68–77
https://doi.org/10.1080/00304948.2020.1834819
EXPERIMENTAL PAPER
1,3,3-Trimethylindolin-5-amine and 4-Formylphenyl
4,4-Dimethylchroman-6-carboxylate
Thiosemicarbazone (OHet72)
Daniel J. Bryant, K. Darrell Berlin, and Richard A. Bunce
Department of Chemistry, Oklahoma State University, Stillwater, Oklahoma
ARTICLE HISTORY Received 3 June 2020; Accepted 29 July 2020
A recent project required the development of efficient syntheses for structures that
could be used to advance our anticancer studies. The first target was 1,3,3-trimethylin-
dolin-5-amine (1, Figure 1), and the second was 4-formylphenyl 4,4-dimethylchroman-
6-carboxylate thiosemicarbazone (2, OHet72). The nitrogen heterocycle 1 was sought as
a building block for the synthesis of a library of anticancer drug analogs, while the
second was a previously reported compound that has recently attracted renewed interest
as an anticancer drug.1,2
Our current lead anticancer compound, SHetA2 (3),3 incorporates a hydrophobic
2,2,4,4-tetramethylthiochroman unit linked via a thiourea to an aromatic ring substi-
tuted at C4 with a polar nitro group. It was anticipated that installation of a relatively
hydrophobic nitrogen heterocycle in place of the thiochroman ring would lead to com-
pounds having similar activity with increased water solubility. We also wished to replace
the nitro group on the linked aromatic ring with other electron-withdrawing substitu-
ents such as trifluoromethyl, trifluoromethoxy and cyano. The chroman 2, first reported
in 1997,4 is a compound we were contracted to prepare in multi-gram quantities. Since
the original synthesis provided 2 in low yield and employed a number of hazardous
reagents,4,5 it was decided to seek a second-generation approach that would increase the
efficiency and allow for safe scale-up. In both of these syntheses, we have developed
approaches that feature an intramolecular reductive Mizoroki-Heck cyclization6,7 under
phase transfer conditions reported by Jeffery.8 Target 1 requires closure of a side-chain
terminal alkene to a 5-membered nitrogen heterocycle whereas target 2 requires closure
of a 6-membered oxygen heterocycle.
The classic Mizoroki-Heck reaction6,7 is characterized by the retention of the alkene
in the cross-coupled product. The regeneration of the alkene results from a b-hydride
elimination, which is considered the thermodynamically favored process.9 In order to
obtain the reduced product, several adjustments were made to the reaction.8,10
Specifically, the addition of formate ion as a hydride source10 and tetrabutylammonium
chloride as a phase-transfer vehicle8 and palladium nanoparticle stabilizing agent,11
allowed a competing mechanism to prevail.12 Using this protocol, b-hydride elimination
competes with ligand exchange of a hydride for a halogen, leading to subsequent C-H
bond formation upon reductive elimination of the catalyst.13 The phase transfer reagent
CONTACT Richard A. Bunce
rab@okstate.edu
Department of Chemistry, Oklahoma State University, Stillwater, Oklahoma
ß 2020 Taylor & Francis Group, LLC

ORGANIC PREPARATIONS AND PROCEDURES INTERNATIONAL
69
Figure 1. Target molecules 1, 2 and lead compound 3.
Scheme 1. The synthesis of 1,3,3-trimethylindolin-5-amine (1). Key: a) Ac2O, AcOH, 84%; b) 3-iodoꢀ-2-
ꢀ
methyl-1-propene, K2CO3, DMF, 60 C, 99%; c) Pd(OAc)2, CH3CO2Na, HCO2Na, Et4NCl, H2O, DMF, 80 C,
85%; d) 20% HCl, 94%; e) NaH, CH3I, DMF, 98%; f) Fe powder, NH4Cl, 4:1 EtOH-H2O, 80%.
also permits the reaction to proceed at lower temperature (80-95 ꢀC) and, in the current
application, tetraethylammonium chloride gave superior results14 compared to the tetra-
butylammonium chloride used in the original disclosure.8
One positive feature of the Jeffery modification is the tolerance and requirement for
the presence of water, thus avoiding the need for rigorously anhydrous reagents and
reaction conditions.14 A second attribute is the ability of the reaction to tolerate various
functional groups.14 This makes the method versatile and potentially very useful in the
synthesis of SHetA2 (3) analogs. The Jeffery conditions are critical to the success of the
required cyclizations. By using this procedure, heterocycles can be synthesized that
include the geminal 3,3- and 4,4-dimethyl groups that are essential to anticancer activity
in heteroarotinoid analogs of 3.
The synthesis of the 1,3,3-trimethylindoline system required six steps (Scheme 1).15
Initially, 2-bromo-4-nitroaniline (4) was treated with acetic anhydride in glacial acetic
acid at room temperature to afford the acetamide product 5 in 84% yield. Subsequent
alkylation of
5
with 3-iodo-2-methyl-1-propene using K2CO3 in N,N-

70
D. J. BRYANT ET AL.
Scheme 2. Second generation synthesis of OHet72 (2). Key: a) EtOH, H2SO4, 86% b) p-TsCl, pyridine,
DCM, 93%; c) K2CO3, DMF, 80 ꢀC, 81%; d) Pd(OAc)2, CH3CO2Na, HCO2Na, Et4NCl, H2O, DMF, 95 ꢀC,
94%; e) KOH, 2:1 EtOH-H2O, 89%; f) 4-HO-C6H4-CHO, EDAC, DMAP, DCM, 90%; g) H2NNHC(S)NH2, 3:1
EtOH-H2O, cat AcOH, 78%.
dimethylformamide (DMF) at 60 ꢀC led to the formation of the tertiary amide 6 in
nearly quantitative yield. Cyclization of 6 via a reductive Mizoroki-Heck reaction
(Pd(OAc)2, CH3CO2Na, HCO2Na, Et4NCl, H2O, 80 ꢀC) afforded the cyclic amide 7 in
85% yield.9 Amide 7 was hydrolyzed with refluxing 20% aqueous HCl (94%), and the
resulting indoline 8 was methylated by treatment with sodium hydride, followed by the
dropwise addition of iodomethane to generate N-methylindoline 9 (98%). Finally,
reduction of the aromatic nitro group in 9 with iron and ammonium chloride in reflux-
ing ethanol–water (4:1) afforded 1,3,3-trimethylindolin-5-amine (1) in 80% yield.16 The
overall yield for the 6-step synthesis was 52%. Conversion of 1 to SHetA2 analogs and
the associated biological studies will be reported in due course.
The previous synthesis4,5 of compound 2 required 7 steps from 3-phenoxypropionic
acid and proceeded in 7.1% overall yield. Our second-generation synthesis of OHet72
(2) also required 7 steps (Scheme 2), but the yield/step was considerably higher [6 linear
steps from 10 (40.9%) or 12 (44.2%)]. Initially, 3-bromo-4-hydroxybenzoic acid (10)
was converted to ester 11 (86%) by refluxing in ethanol containing H2SO4 as a catalyst.
3-Methyl-3-buten-1-ol (12) was converted to its p-toluenesulfonate 13 (93%) using p-
toluenesulfonyl chloride and pyridine in dichloromethane (DCM). The hydroxy group
in 11 was alkylated with 13 using K2CO3 in DMF at 80 ꢀC to produce ether 14 in 81%
yield. Subsequent cyclization of 14 using a reductive Mizoroki-Heck reaction under
Jeffery conditions (as above, 95 ꢀC) afforded chroman ester 15 in 94% yield. Ester 15
was then hydrolyzed to carboxylic acid 16 (89%) with KOH in ethanol–water (2:1).
Coupling of acid 16 with 4-hydroxybenzaldehyde mediated by 1-ethyl-3-(3-dimethyl-
aminopropyl)carbodiimide hydrochloride (EDAC) and 4-dimethylaminopyridine
(DMAP) in DCM yielded the chroman ester-aldehyde 17 (90%). Finally, conversion of
17 to OHet72 (2, 78%) was accomplished by adding a warm aqueous solution of thio-
semicarbazide and acetic acid to a warm solution of 17 in ethanol. The current

ORGANIC PREPARATIONS AND PROCEDURES INTERNATIONAL
71
procedure utilized fewer corrosive reagents and afforded the desired compound in excel-
lent overall yield. Since we needed OHet72 in batches larger than 10 g, this method
proved to be a much more efficient process, and the cost was still reasonable.
The current article reports the synthesis of compounds 1 and 2 for use in our anti-
cancer drug research program. The syntheses both utilize a Jeffrey modification of the
Mizoroki-Heck reaction for heterocycle formation. The overall yields are good to excel-
lent and will allow the efficient preparation of these materials in multi-gram quantities.
Experimental section
Commercial anhydrous N,N-dimethylformamide (DMF) was stored under dry N2 and
transferred by syringe into reactions when needed. Tetrahydrofuran (THF) was distilled
from lithium aluminum hydride prior to use. All other commercial reagents and sol-
vents were used as received. Unless otherwise indicated, all reactions were carried out
under dry N2 in oven-dried glassware. Reactions were monitored by thin layer chroma-
tography (TLC, Analtech No 21521) using silica gel GF plates, and compound elution
was followed using a hand-held UV lamp. Melting points were uncorrected. IR spectra
1
were run as thin films on NaCl disks. The H- and 13C-NMR spectra were measured in
the indicated solvent at 400 MHz and 101 MHz, respectively, using tetramethylsilane as
the internal standard with coupling constants (J) given in Hz. Mass spectra (EI) were
measured at 30 eV. Elemental analyses ( 0.4%) were performed by Atlantic Microlabs,
Norcross, GA.
N-(2-Bromo-4-nitrophenyl)acetamide (5)
2-Bromo-4-nitroaniline (4, 5.00 g, 1.0 equiv, 23.0 mmol) was dissolved in acetic acid
(50 mL), and acetic anhydride (10.8 g, 10 mL, 4.6 equiv, 106 mmol) was added. The mix-
ture was stirred at room temperature for 18 h, at which time TLC analysis (1:1 ether-
hexane) indicated complete consumption of the starting material. The reaction mixture
was poured into water (100 mL), at which time a yellow precipitate formed rapidly. The
precipitate was collected by vacuum filtration and washed with copious amounts of
water. The solid was dried under vacuum to yield 5 (5.01 g, 84%) as a yellow solid, mp
1
119-120 ꢀC. IR: 3216, 1656, 1589, 1521, 1313 cmꢁ1; H NMR (400 MHz, CDCl3): d 8.66
(d, J ¼ 9.2 Hz, 1H), 8.46 (d, J ¼ 2.5 Hz, 1H), 8.26 (dd, J ¼ 9.2, 2.5 Hz, 1H), 7.89 (br s,
1H), 2.32 (s, 3H); 13C NMR (101 MHz, CDCl3): d 168.5, 143.2, 141.3, 127.9, 124.2,
120.2, 11.8, 25.2; MS (EI): m/z 258, 260 (ca 1:1, Mþꢂ).
Anal. Calcd for C8H7BrN2O3: C, 37.09: H, 2.72: N, 10.81. Found: C, 37.17; H, 2.75;
N, 10.79.
N-(2-Bromo-4-nitrophenyl)-N-(2-methyl-2-propenyl)acetamide (6)
N-(2-Bromo-4-nitrophenyl)acetamide (5, 5.00 g, 1.0 equiv, 19.3 mmol) was dissolved in
DMF (60 mL), and anhydrous K2CO3 (10.6 g, 4.0 equiv, 77.2 mmol) was added. The
mixture was stirred at room temperature under N2 for 10 min, at which time 3-iodo-2-
methyl-1-propene (7.00 g, 2.0 equiv, 38.6 mmol) was added in one portion. The mixture
was heated to 60 ꢀC for 18 h, after which TLC analysis (1:2 ether-hexane) indicated the

72
D. J. BRYANT ET AL.
reaction was complete. The crude reaction mixture was poured into water (100 mL) and
extracted with EtOAc (3 ꢃ 75 mL). The combined organic extracts were washed with
water (2 ꢃ 75 mL) and aqueous NaCl (75 mL), dried (Na2SO4), and concentrated under
1
vacuum to afford 6 (6.02 g, 99%) as an orange oil. IR: 1652, 1583, 1513, 1317 cmꢁ1; H
NMR (400 MHz, CDCl3): d 8.59 (d, J ¼ 2.5 Hz, 1H), 8.24 (dd, J ¼ 8.6, 2.5 Hz, 1H), 7.41
(d, J ¼ 8.6 Hz, 1H), 4.96 (d, J ¼ 14.5 Hz, 1H), 4.86 (s, 1H), 4.66 (s, 1H), 3.52 (d,
J ¼ 14.5 Hz, 1H), 1.87 (s, 3H), 1.81 (s, 3H); 13C NMR (101 MHz, CDCl3): d 169.2, 147.5,
147.2, 140.0, 131.5, 129.2, 124.8, 123.5, 115.0, 52.7, 22.6, 20.6; MS (EI): m/z 312, 314 (ca
1:1, Mþꢂ).
Anal. Calcd for C12H13BrN2O3: C, 46.03: H, 4.18: N, 8.95. Found: C, 46.08; H, 4.20;
N, 8.90.
1-(3,3-Dimethyl-5-nitroindolin-1-yl)ethan-1-one (7)
N-(2-Bromo-4-nitrophenyl)-N-(2-methyl-2-propenyl)acetamide (6, 4.40 g, 1.0 equiv,
14.0 mmol) was dissolved in DMF (50 mL), and sodium acetate (2.84 g, 2.5 equiv,
35.0 mmol), sodium formate (1.19 g, 1.25 equiv, 17.5 mmol), and tetraethylammonium
chloride (2.78 g, 1.2 equiv, 16.8 mmol) were added sequentially to form a slurry. Water
(0.5 mL) and Pd(OAc)2 (0.31 g, 0.1 equiv, 1.4 mmol, 10 mol%) were added, and the reac-
tion mixture was heated to 80 ꢀC under N2 for 18 h. The reaction mixture was cooled,
filtered through a 2 cm Celite pad and then partitioned between water (150 mL) and
EtOAc (100 mL). The aqueous layer was washed with EtOAc (2 ꢃ 100 mL), and the
combined organic layers were washed with water (2 ꢃ 50 mL), aqueous NaCl (75 mL),
and then dried (Na2SO4). Concentration under vacuum afforded 7 (2.78 g, 85%) as a
1
yellow solid, mp 183-184 ꢀC. IR: 1674, 1571, 1375 cmꢁ1; H NMR (400 MHz, CDCl3): d
8.59 (d, J ¼ 9.0 Hz, 1H), 8.15 (dd, J ¼ 9.0, 2.4 Hz, 1H), 8.00 (d, J ¼ 2.4 Hz, 1H), 3.91 (s,
2H), 2.28 (s, 3H), 1.42 (s, 6H); 13C NMR (101 MHz, CDCl3): d 169.6, 146.9, 143.9,
141.7, 124.9, 118.0, 116.4, 64.1, 40.1, 28.7, 24.3; MS (EI): m/z 234 (Mþꢂ).
Anal. Calcd for C12H14N2O3: C, 61.53: H, 6.02: N, 11.96. Found: C, 61.57; H, 6.04;
N, 11.88.
3,3-Dimethyl-5-nitroindoline (8)
1-(3,3-Dimethyl-5-nitroindolin-1-yl)ethan-1-one (7, 2.70 g, 11.5 mmol) was added to
20% HCl (50 mL), and the mixture was heated to 100 ꢀC. After 1 h, all of the solid had
dissolved, indicating the reaction was complete. The mixture was poured into 1 M
NaOH (150 mL). The aqueous mixture was extracted with EtOAc (3 ꢃ 75 mL). The
combined organic layers were washed with aqueous NaCl (100 mL), dried (Na2SO4),
and concentrated under vacuum to afford 8 (2.07 g, 94%) as a yellow solid, mp 74-
76 ꢀC. IR: 3388, 1558, 1363 cmꢁ1
2.3 Hz, 1H), 7.90 (d, J ¼ 2.3 Hz, 1H), 6.49 (d, J ¼ 8.7 Hz, 1H), 4.45 (br s, 1H), 3.49 (s,
2H), 1.35 (s, 6H); 13C NMR (100 MHz, CDCl3): d 155.9, 139.2, 138.2, 126.1, 118.9,
106.6, 61.7, 41.1, 27.9; MS (EI): m/z 192 (Mþꢂ).
;
1H NMR (400 MHz, CDCl3): d 8.03 (dd, J ¼ 8.7,
Anal. Calcd for C10H12N2O2: C, 62.49: H, 6.29: N, 14.57. Found: C, 62.56; H, 6.31;
N, 14.55.

ORGANIC PREPARATIONS AND PROCEDURES INTERNATIONAL
73
1,3,3-Trimethyl-5-nitroindoline (9)
A suspension of oil-free NaH in DMF was prepared by washing a 60% mineral oil sus-
pension of NaH (0.25 g, 1.15 equiv, 6.00 mmol) with hexane (3 ꢃ 5 mL) and then dilut-
ing with DMF (5 mL). 3,3-Dimethyl-5-nitroindoline (8, 1.0 g, 5.21 mmol), dissolved in
DMF (10 mL), was added dropwise at room temperature to the NaH suspension over
5 min. After the base was consumed, a solution of iodomethane (0.81 g, 0.36 mL, 1.1
equiv, 5.70 mmol) in DMF (5 mL) was added dropwise. The reaction mixture was
heated to 40 ꢀC for 1 h, at which time TLC analysis (1:2 ether-hexane) indicated com-
plete consumption of the starting material. The reaction was quenched slowly with
aqueous NaCl (50 mL) and extracted with EtOAc (3 ꢃ 50 mL). The combined organic
layers were washed with water (3 ꢃ 30 mL), aqueous NaCl (30 mL), dried (Na2SO4), and
concentrated under vacuum to afford 9 (1.05 g, 98%) as a yellow oil. IR: 1551,
1359 cmꢁ1
;
1H NMR (400 MHz, CDCl3): d 8.08 (dd, J ¼ 8.8, 2.3 Hz, 1H), 7.83 (d,
J ¼ 2.3 Hz, 1H), 6.29 (d, J ¼ 8.8 Hz, 1H), 3.36 (s, 2H), 2.92 (s, 3H), 1.35 (s, 6H); 13C
NMR (101 MHz, CDCl3): d 155.9, 139.2, 138.2, 126.1, 118.9, 106.6, 61.7, 41.1, 37.4, 27.9;
MS (EI): m/z 206 (Mþꢂ).
Anal. Calcd for C11H14N2O2: C, 64.06: H, 6.84: N, 13.58. Found: C, 64.15; H, 6.82;
N, 13.52.
1,3,3-Trimethylindolin-5-amine (1)
The general procedure of Zhao and coworkers15 was followed. 1,3,3-Trimethyl-5-nitro-
indoline (9, 1.05 g, 1.0 equiv, 5.10 mmol) was placed in an EtOH-water mixture (4:1,
60 mL). Iron powder (1.15 g, 4.0 equiv, 20.5 mmol) and NH4Cl (0.35 g, 1.3 equiv,
6.54 mmol) were added, and the mixture was heated at 85 ꢀC for 2 h, after which time
TLC analysis (1:1 ether-hexane) indicated complete consumption of the starting mater-
ial. The reaction mixture was filtered through a 2 cm Celite pad, which was washed
with additional EtOH (15 mL). The volume of the filtrate was reduced under vacuum,
and then the mixture was diluted with saturated NaHCO3 (100 mL). The aqueous layer
was extracted with EtOAc (3 ꢃ 50 mL), and the combined organic extracts were washed
with an aqueous NaHCO3 and NaCl mixture (1:1, 50 mL), and dried (Na2SO4). The
solvent was removed under vacuum to afford 1 (0.72 g, 80%) as a purple oil. IR: 3421,
1
3347 cmꢁ1; H NMR (400 MHz, CDCl3): d 6.49 (dd, J ¼ 7.5 Hz, 1H), 6.47 (s, 1H), 6.36
(d, J ¼ 7.5 Hz, 1H), 3.23 (br s, 2H), 2.96 (s, 2H), 2.67 (s, 3H), 1.26 (s, 6H); 13C NMR
(101 MHz, CDCl3): d 145.5, 140.8, 138.5, 114.3, 110.4, 108.7, 71.1, 40.4, 37.4, 27.1; MS
(EI): m/z 176 (Mþꢂ).
Anal. Calcd for C11H16N2: C, 74.96; H, 9.15; N, 15.89. Found: C, 75.01; H, 9.18;
N, 15.83.
Ethyl 3-bromo-4-hydroxybenzoate (11)
Note: This is a commercial compound, but very expensive. 3-Bromo-4-hydroxybenzoic
acid (10, 15.0 g, 69.1 mmol) was dissolved in EtOH (200 mL), and concentrated H2SO4
(1 mL) was added. The solution was heated at reflux for 3 days, and then the solvent
was removed under vacuum. The residue was poured into water (200 mL), and the

74
D. J. BRYANT ET AL.
aqueous layer was extracted with ether (3 ꢃ 150 mL). The combined organic layers were
washed with saturated aqueous NaHCO3 (50 mL) and aqueous NaCl (100 mL), and then
dried (Na2SO4). Concentration under vacuum gave 11 (14.6 g, 86%) as a white solid,
1
mp 102-104 ꢀC (lit17 mp 102-103 ꢀC). IR: 3244, 1677 cmꢁ1; H NMR (400 MHz, CDCl3):
d 8.19 (d, J ¼ 2.0 Hz, 1H), 7.93 (dd, J ¼ 8.5, 2.0 Hz, 1H), 7.05 (d, J ¼ 8.5 Hz, 1H), 5.92
(br s, 1H), 4.35 (q, J ¼ 7.1 Hz, 2H), 1.38 (t, J ¼ 7.1 Hz, 3H); 13C NMR (101 MHz,
CDCl3): d 165.1, 156.0, 133.8, 131.0, 124.4, 115.7, 110.0, 61.1, 14.3; MS (EI): m/z 242,
244 (ca 1:1, Mþꢂ).
3-Methyl-3-buten-1-yl p-toluenesulfonate (13)
3-Methyl-3-buten-1-ol (12, 12.5 g, 14.4 mL, 1.0 equiv, 145.3 mmol) was dissolved in
DCM (150 mL), and the solution was cooled to 0 ꢀC. Pyridine (23.7 g, 24.2 mL, 2.05
equiv, 300.0 mmol) was added in one portion, followed by dropwise addition of a solu-
tion of p-toluenesulfonyl chloride (27.2 g, 0.98 equiv, 142.5 mmol) in DCM (50 mL) over
20 min. The mixture was allowed to slowly warm to room temperature with stirring
overnight. The crude reaction mixture was washed with water (3 ꢃ 100 mL), aqueous
NH4Cl (150 mL), aqueous NaCl (100 mL), and then dried (Na2SO4). The solvent was
removed under vacuum to afford 13 (31.7 g, 93%) as a pale yellow liquid. The spectra
matched those reported previously.18
Ethyl 3-bromo-4-((3-methyl-3-buten-1-yl)oxy)benzoate (14)
Ethyl 3-bromo-4-hydroxybenzoate (11, 14.5 g, 1.0 equiv, 59.2 mmol) and 3-methyl-3-
buten-1-yl p-toluenesulfonate (13, 14.2 g, 1.0 equiv, 59.2 mmol) were dissolved in DMF
(50 mL), and K2CO3 (32.7 g, 4.0 equiv, 237.0 mmol) was added. The reaction mixture
was stirred under N2 at 80 ꢀC for 18 h, at which time TLC analysis (1:2 ether-hexane)
indicated complete consumption of the starting phenol. The reaction mixture was
cooled to room temperature and then poured into water (200 mL). The aqueous layer
was extracted with ether (3 ꢃ 100 mL), and the combined organic layers were washed
with water (3 ꢃ 100 mL), saturated aqueous NaHCO3 (100 mL), aqueous NaCl (100 mL),
and then dried (Na2SO4). Removal of the solvent under vacuum gave 14 (15.0 g, 81%)
as a colorless oil. IR: 1712, 1645 cmꢁ1 1H NMR (400 MHz, CDCl3): d 8.22 (d,
;
J ¼ 2.1 Hz, 1H), 7.96 (dd, J ¼ 8.6, 2.1 Hz, 1H), 6.90 (d, J ¼ 8.6 Hz, 1H), 4.88 (s, 1H), 4.82
(s, 1H), 4.35 (q, J ¼ 7.1 Hz, 2H), 4.19 (t, J ¼ 6.8 Hz, 2H), 2.59 (t, J ¼ 7.1 Hz, 2H), 1.85 (s,
3H), 1.38 (t, J ¼ 7.1 Hz, 3H); 13C NMR (101 MHz, CDCl3): d 165.3, 158.8, 141.7, 134.8,
130.5, 124.0, 112.6, 111.8, 111.7, 68.1, 61.0, 36.9, 23.0, 14.3; MS (EI): m/z 312, 314 (ca
1:1, Mþꢂ).
Anal. Calcd for C14H17BrO3: C, 53.69; H, 5.47. Found: C, 53.73; H, 5.46.
Ethyl 4,4-dimethylchroman-6-carboxylate (15)
Ethyl 3-bromo-4-((3-methyl-3-buten-1-yl)oxy)benzoate (14, 14.8 g, 1.0 equiv, 47.3 mmol)
was dissolved in DMF (30 mL), and sodium acetate (9.60 g, 2.5 equiv, 117 mmol),
sodium formate (4.02 g, 1.25 equiv, 59.1 mmol), and tetraethylammonium chloride

ORGANIC PREPARATIONS AND PROCEDURES INTERNATIONAL
75
(9.37 g, 1.2 equiv, 56.6 mmol) were added sequentially to form a slurry. Water (2 mL)
and Pd(OAc)2 (1.06 g, 0.1 equiv, 0.47 mmol, 10 mol%) were added, and the reaction
mixture was heated at 95 ꢀC under N2 for 18 h. The mixture was cooled, filtered
through a 2 cm Celite pad, and then partitioned between water (200 mL) and ether
(100 mL). The aqueous layer was extracted with ether (2 ꢃ 100 mL), and the combined
organic layers were washed with water (3 ꢃ 100 mL), aqueous NaCl (100 mL), and then
dried (Na2SO4). The solvent was removed under vacuum to afford 15 (10.4 g, 94%) as a
1
colorless oil. IR: 1695 cmꢁ1; H NMR (400 MHz, CDCl3): d 8.00 (d, J ¼ 2.1 Hz, 1H),
7.75 (dd, J ¼ 8.6, 2.1 Hz, 1H), 6.79 (d, J ¼ 8.6 Hz, 1H), 4.34 (q, J ¼ 7.1 Hz, 2H), 4.24 (t,
J ¼ 5.3 Hz, 2H), 1.85 (t, J ¼ 5.4 Hz, 2H), 1.37 (t, J ¼ 7.1 Hz, 3H), 1.36 (s, 6H); 13C NMR
(101 MHz, CDCl3): d 166.7, 157.7, 131.4, 129.1, 128.8, 122.5, 116.9, 63.4, 60.6, 37.1, 30.8,
30.6, 14.4; MS: m/z 234 (Mþꢂ).
Anal. Calcd for C14H18O3: C, 71.77; H, 7.74. Found: C, 71.72; H, 7.74.
4,4-Dimethylchroman-6-carboxylic acid (16)
Ethyl 4,4-dimethylchroman-6-carboxylate (15, 10.0 g, 1.0 equiv, 42.7 mmol) was placed
in an EtOH-water mixture (2:1, 150 mL), and KOH (4.8 g, 2.0 equiv, 85.7 mmol) was
added. The reaction was stirred at 80 ꢀC for 3 h, at which time TLC analysis (ether)
indicated the reaction was complete. The volume was reduced under vacuum, the resi-
due was acidified with 1 M HCl to pH 2, and then the aqueous layer was extracted with
DCM (3 ꢃ 100 mL). The combined organic layers were washed with aqueous NaCl
(100 mL), dried (Na2SO4), and concentrated under vacuum to afford 16 (7.85 g, 89%) as
a white solid, mp 226-228 ꢀC (lit4 mp 227.5-228.5). The spectral data matched those
reported previously.4
4-Formylphenyl 4,4-dimethylchroman-6-carboxylate (17)
4,4-Dimethylchroman-6-carboxylic acid (16, 7.54g, 1.0 equiv, 36.6 mmol) and 4-hydroxy-
benzaldehyde (4.46g, 1 equiv, 36.6mmol) were dissolved in DCM (200 mL). 4-
Dimethylaminopyridine (11.2g, 2.5 equiv, 91.8mmol) was added, followed by 1-ethyl-3-
(3-dimethylaminopropyl)carbodiimide hydrochloride (7.02g, 1.0 equiv, 36.6mmol). The
reaction mixture was stirred at 23 ꢀC for 24 h and then washed with 1 M HCl
(2 ꢃ 100 mL), saturated aqueous NaHCO3 (100 mL) and aqueous NaCl (100 mL), and
then dried (Na2SO4). Concentration under vacuum afforded a tan, oily solid that was
recrystallized from EtOH (15 mL) to afford 17 (10.2 g, 90%) as a cream-colored solid,
mp 131-132 ꢀC (lit4 mp 132-133.5 ꢀC). The spectral data matched those reported
previously.4
4-Formylphenyl 4,4-Dimethylchroman-6-carboxylate Thiosemicarbazone (2)
4-Formylphenyl 4,4-dimethylchroman-6-carboxylate (17, 3.0 g, 1.0 equiv, 9.7 mmol) was
suspended in ethanol (180 mL), and the mixture was heated to 70 ꢀC until a clear solu-
tion was formed. To this warm solution was added a warm solution of thiosemicarba-
zide (0.97 g, 1.1 equiv, 10.6 mmol) in water (57 mL). Three drops of glacial acetic acid

76
D. J. BRYANT ET AL.
were added, and the solution was allowed to cool to room temperature with stirring
overnight. At this time, white crystals were noted in the flask, and the mixture was fur-
ther cooled to –20 ꢀC for 24 h. The mixture was warmed to room temperature for 1 h
before collecting the crystals by vacuum filtration. The white solid was dried under vac-
uum overnight to afford 2 (2.88 g, 78%), mp 187-189 ꢀC (lit4 mp 185-186 ꢀC). The spec-
tra for this compound closely matched the previous report.4 IR: 3436, 3402, 3263, 3166,
1
1729, 1601 cmꢁ1; H NMR (400 MHz, DMSO-d6): d 11.47 (s, 1H), 8.22 (br s, 1H), 8.09
(superimposed d, J ¼ 1.8 Hz, 1H and s, 1H), 8.06 (br s, 1H), 7.91 (d, J ¼ 8.6 Hz, 2H),
7.85 (dd, J ¼ 8.6, 1.8 Hz, 1H), 7.31 (d, J ¼ 8.6 Hz, 2H), 6.92 (d, J ¼ 8.6 Hz, 1H), 4.28 (t,
J ¼ 5.4 Hz, 2H), 1.86 (t, J ¼ 5.4 Hz, 2H), 1.35 (s, 6H); 13C NMR (101 MHz, DMSO-d6): d
178.5, 164.7, 158.7, 152.3, 141.8, 132.5, 132.4, 129.8, 129.7, 128.9, 122.8, 121.0, 117.7,
63.7, 36.6, 30.8, 30.7; MS: m/z 383 (Mþꢂ).
Anal. Calcd for C20H21N3O3S: C, 62.64; H, 5.52; N, 10.96. Found: C, 62.72; H, 5.54;
N, 10.89.
Acknowledgments
The project directors (R.A.B and K.D.B.) gratefully acknowledge the support of this research by
the Stephenson Cancer Research Center/Oklahoma Tobacco Settlement Endowment Trust
(TSET). The authors are also indebted to the Oklahoma State University College of Arts and
Sciences for funds to purchase several departmental instruments including an FT-IR and a
400 MHz NMR unit for the Statewide NMR facility. This NMR facility was initially established
with support from NSF (BIR-9512269), the Oklahoma State Regents for Higher Education, the
W. M. Keck Foundation, and Conoco, Inc.
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