Alternative synthesis of the anti-baldness compound RU58841

Article abstract of DOI:10.1039/c4ra00332b

RU58841 is active against baldness and is commercially available. The previously reported synthesis uses phosgene, three discrete inert atmosphere steps and three steps that require flash chromatography. Our synthesis uses no phosgene, only one inert atmosphere step and does not require flash chromatography. This is achieved by stepwise construction of the hydantoin moiety around the amino group of 3-trifluoromethyl-4-cyanoaniline and ring closure to give a 2-nitropropane leaving group. On a small scale we achieved an overall yield of 33%.

Full text of DOI:10.1039/c4ra00332b

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Alternative synthesis of the anti-baldness
compound RU58841†
Cite this: RSC Adv., 2014, 4, 14143
Matthew J. Leonard, Anthony R. Lingham, Julie O. Niere, Neale R. C. Jackson,
Peter G. McKay and Helmut M. Hugel
¨
RU58841 is active against baldness and is commercially available. The previously reported synthesis uses
phosgene, three discrete inert atmosphere steps and three steps that require flash chromatography. Our
synthesis uses no phosgene, only one inert atmosphere step and does not require flash chromatography.
This is achieved by stepwise construction of the hydantoin moiety around the amino group of 3-
trifluoromethyl-4-cyanoaniline and ring closure to give a 2-nitropropane leaving group. On a small scale
we achieved an overall yield of 33%.
Received 13th January 2014
Accepted 6th March 2014
DOI: 10.1039/c4ra00332b
www.rsc.org/advances
In the 1970s, T. Battmann and co-workers at the French
pharmaceutical company Roussel-Uclaf explored hydantoin
Introduction
compounds to treat a number of ailments. They prepared
RU58841 (Fig. 1), which was targeted as a prostate cancer
treatment,4 but biological testing with rats produced hair
growth. Roussel-Uclaf prepared homologues of RU58841 (Fig. 3)
including RU58642 (a hydantoin) and RU56187 (a thio-
hydantoin) which were both found to be active non-steroidal
anti-androgens.5
While RU58642 had a stronger anti-androgen effect than
RU58841, its side effects made it unusable in patients. RU58642
has since found use in biochemical research into the androgen
receptor.6,7
Hydantoins are ve-membered heterocycles with four points of
functionality (Fig. 1).
They are a staple scaffold displayed in many compounds
with functional end use such as cosmetics, shampoos and skin
lotions. Important medicinal compounds that incorporate the
hydantoin moiety include phenytoin (antiepileptic) and niluta-
mide (anticancer)1 (Fig. 2). The chiral hydantoin compound
(+)-hydantocidin (Fig. 2) is extracted from Streptomyces hygro-
scopicus and is a potent herbicide.2
Given the common occurrence of hydantoins in a diverse
range of compounds, alternative hydantoin syntheses are
potentially useful. Recent additions include access to 5,5-
disubstituted hydantoins by treatment of nitriles with an
organometallic reagent (RLi or RMgX) followed by KCN/
(NH4)2CO3 (ref. 1) and use of carbodiimides to prepare inter-
mediates that form hydantoins by ring closure and
rearrangement.3
Research interest in anti-androgen pharmaceuticals thrived
in the following decades. In 1994 Battmann et al. published
biological evaluation of both RU58841 and RU56187 (ref. 5) and
Fig. 2 Biologically-active hydantoin compounds.
Fig. 1 Hydantoin group and RU58841 anti-baldness compound.
RMIT University, 1 Bowen street, Melbourne 3001, Australia. E-mail: Matthew.
Leonard742@gmail.com
† Electronic supplementary information (ESI) available. CCDC 892388, 893326,
894556 and 904089. For ESI and crystallographic data in CIF or other electronic
format see DOI: 10.1039/c4ra00332b
Fig. 3 RU58642 and RU56187.
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hydantoin moiety (compound 6) which yields 2-nitropropane
as a side product. The hydantoin 6 is then alkylated with
4-bromobutyl acetate using NaH/halogen coupling and depro-
tected by addition of NaOH to the same pot to furnish the
product – RU58841 (Fig. 5).
During our efforts to access the RU58841 synthon 6 without
using phosgene we discovered that, unexpectedly, reaction of
the tertiary bromide 1 with excess sodium nitrite in DMF at
room temperature produced an 86% yield of the stable nitro
compound 2. Such a reaction at a tertiary carbon appears to
have no literature precedent. The generality of this synthetically
useful reaction is being explored and will be reported soon.
Upon discovery that the bromine had been substituted with
a nitro group, this appeared a safer and more convenient
approach to access to the desired hydantoin 6 for RU58841 than
the synthesis reported by Battmann et al. (Fig. 4). In keeping
with our aim to use less toxic reagents that are easy to handle,
this new scheme (Fig. 5) achieves the hydantoin 6 and thence
RU58841 by way of ‘reacylation’ of 3, bromo-nitro substitution
to furnish 5 in situ and then a ring closure of 5 with 2-nitro-
propane acting as the leaving group. Thus we present a simple
new hydantoin preparation exemplied by the synthesis of
compound RU58841 in 33% overall yield.
Fig. 4 Traditional synthesis of RU58841.
their synthesis of RU58841.4 They prepared the hydantoin by
rst reacting 3-triuoromethyl-4-cyanoaniline with phosgene to
produce an isocyanate intermediate (Fig. 4). The 1994 paper4
reported that the dose required for hair regrowth was only one
third of that required to give systemic side effects making
RU58841 viable as a topical anti-androgen.4 Further work by De
Brouweri et al. conrmed the effect of RU58841 as an anti-
androgen and baldness treatment by observing hair re-growth
on bald human scalp segments that had been graed to mice.8
As well as empirical studies, the biochemistry of RU58841 and
other hydantoins have been evaluated for their effect as non-
steroidal testosterone inhibitors.9
Bromine-nitro substitution
As the synthesis of RU58841 by Battmann et al. (Fig. 4) uses Compound 2 was prepared by placing 1 in DMF with a 4–10
molar excess of NaNO2. It was stirred at RT for 14 h with no
effort made to keep anhydrous conditions. When the reaction
was seen to be complete by TLC, a volume of water equal to the
volume of DMF used was added and the ask allowed to sit for 1
hour. For a more complete crystallization, the ask was placed
into a fridge at 8 ꢁC overnight. The crystals were ltered for an
phosgene (a toxic gas which requires a high level of expertise
with handling), alternative preparations have been sought.
¨
In 2006 Hugel et al. prepared RU58841 by N-arylation of
5,5-dimethylhydantoin.10 They achieved the RU58841 hydantoin
synthon in 55% yield by NaH/halogen aryl-coupling of
5,5-dimethylhydantoin with 3-triuoromethyl-4-cyanoaniline
but the yield lowered to 30% when carried out on a 10 g scale. apparent 122% yield which was due to the co-crystallization of
Replacing this NaH coupling with copper acetate promoted DMF with the product in a 1 : 1 ratio.†
boronic acid coupling gave a 79% yield of the same synthon.10
When this method was tried using other anilines the yields were
limited to ꢀ50% and yields above 60% could only be achieved
when the aniline being attached to the hydantoin had either
nitrile or methoxy substituents.11
To improve on the RU58841 syntheses by Battmann et al. and
Hugel et al., in lieu of aryl-coupling we now present an approach esters rather than nitro compounds.13 We believe neither
which uses the same start material as Battmann et al.4 mechanism to be operative here. This general reaction has been
Compound 2 is an a-nitroisobutyranilide. This class of
compounds has been described before only once12 where they
were prepared by a different and more complex route. Bromine-
nitro substitution from exposure to nitrite ions is unexpected
for compound 1, as SN2 reactions at tertiary carbons are virtually
unknown,13 while SN1 reactions of nitrite normally give nitrite
explored and will be discussed elsewhere.
(3-triuoromethyl-4-cyanoaniline) but builds the hydantoin
moiety around the aniline so as to avoid the carbonylation step
which requires either the highly toxic gas phosgene or phosgene
equivalents reagents which are difficult to upscale and still
somewhat toxic. This provides a more exible synthesis than
the boronic acid coupling approach by Hugel et al. as it is
Ring closure to prepare hydantoin compound (6)
A number of room temperature methods with catalysts were
tried, however the cleanest method for ring closure of 5 proved
transferable to the preparation of a wider variety of other to be heating while still in the DMF from the previous step at
hydantoin target compounds.
110 ꢁC for 7 h. GC-MS showed a major peak (89% of total peak
area). Workup gave a white solid (compound 6, 92% crude yield)
that was used for further reaction without recrystallization.
This ring closure provides a new way to prepare N-aryl
Results and discussion
Starting from 3-triuoromethyl-4-cyanoaniline, our six step hydantoins. It also yields 2-nitropropane as a leaving group
synthesis prepares a long chain double-amide intermediate which is of interest as it has not (to the best of our knowledge)
which undergoes a ring closure to give the stable ve membered been reported as a leaving group before.
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Fig. 5 Alternative synthesis of RU58841.
Two alternative mechanisms can be envisaged for this cyc- NMR chemical shis for each compound differed slightly from
lisation both of which adhere to the Baldwin rules. The anilide those reported; this may be due to a difference in solvent as
nitrogen could perform an acyl substitution at the other Battmann et al. did not report their solvent or compound
carbonyl in a 5-exo-trig attack, with loss of 2-nitropropane concentration. We report the 13C NMR data for both
anion. However the high steric hindrance about this amide compounds for the rst time. Our melting point for 6 matched
carbonyl makes this seem unlikely. Alternatively, the 2-nitro- that reported, but we have repeatedly obtained a melting point
ꢁ
propane anion could be lost rst to create a much more elec- for RU58841 of 71–72 C from highly crystalline samples that
trophilic, much less hindered isocyanate, which would then be are pure by C, H, N analysis, while Battmann et al. report 103–
attacked in a 5-exo-dig geometry (Fig. 6).
104 ꢁC. Our 1H and 13C NMR of RU58841 gave three minor
This mechanism is supported by our observation that the peaks which could not be assigned to the compound at d 6.7 in
a-nitroisobutyranilide 2 appears to be converted by injection 1H NMR and at d 116.3 and d 151 in the 13C NMR. These are
into a conventional mass spectrometer into the corresponding possible due to a tautomeric impurity present at very low levels,
isocyanate, with loss of 2-nitropropane. The dipolar/partial such that it does not affect the results of C, H, N analysis.
ionic nature of DMF may help to stabilize the amide and
encourage the anilide nitrogen to proceed via the isocyanate
mechanistic pathway. This represents a novel isocyanate prep-
aration and will be further studied to be reported elsewhere.
We have added to the range of hydantoin syntheses with a
Conclusions
synthesis of RU58841 in a 33% overall yield. An a-isobutyryl
bromide exposed to nitrite ions was shown to readily and
cleanly convert to its equivalent a-isobutyryl nitro compound.
Comparison of RU58841 and its synthon (6) with literature
data
The RU58841 and compound 6 prepared by us had identical UV This demonstrates that bromine-nitro substitutions do occur
and IR properties to those reported by Battmann et al.4 Our 1H on tertiary carbons with
a
neighbouring carbonyl.
Fig. 6 Probable mechanism for hydantoin formation.
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2-Nitropropane was shown to be an effective leaving group, J 2), d 8.73 (br, s, NH); 13C NMR (75 MHz, 40 mg: 0.4 mL
enabling the formation of a hydantoin ring by cyclization. This DMSOd6): d 31.3 (s, C-3A/B), d 60.6 (s, C-2), d 103.3 (s, C-40),
method of achieving a hydantoin ring may be used to prepare a d 116.7 (s, CN), d 118.5 (q, C-20, J 5), d 123.4 (q, CF3, J 136), d 123.7
suite of hydantoins for testing or to achieve an alternative end- (s, C-60), d 132.6 (q, C-30, J 32), d 137.1 (s, C-50), d 144.4 (s, C-10),
use hydantoin.
d 171.3 (s, C-1); Neg ESI HRMS: calcd for C12H10N2OF3Br
(M ꢂ H): 332.9850, observed: m/z 332.9858.†
Experimental section
General methods
N-[4-Cyano-3-(triuoromethyl)phenyl]-2-methyl-2-
nitropropanamide (compound 2)
Chemicals were used unaltered from the following suppliers: 3-
triuoromethyl-4-cyanoaniline (AK Scientic); a-bromoisobu-
tyryl bromide (Sigma-Aldrich); 1,2-dichloroethane (BDH);
toluene–n-heptane–NaNO2 (Ajax); DMF–ethyl acetate–methanol
(Chem-Supply); tert-butyl methyl ether–pentane (Merck). K2CO3
(Ajax) was stored in oven at 115 ꢁC before use. TLC plates from
Merck were labelled “TLC silica gel 60 F254”. The dry DMF used
for step 7 was obtained from a solvent dispensing system
immediately before use, but DMF used in steps 2 and 5 was used
unaltered from the bottle (Chem-Supply).
Compound 1 (5.00 g, 15.0 mmol) was dissolved in DMF
(130 mL) and NaNO2 (10.0 g, 145 mmol) was added. The
contents were stirred at room temperature for 14 h then
transferred to a larger ask where deionized water (130 mL) was
added which gave heat and produced white needles that were
ltered and washed with water to give 4.84 g of 2 that were
shown to be co-crystallized in a 1 : 1 ratio with DMF and
therefore contained 12.9 mmol of 2 for a corrected yield of 86%,
mp 129–131 ꢁC (co-crystallized with DMF); Rf ¼ 0.79 in 1 : 1
hexanes–EtOAc or 0.17 in 4 : 1 hexanes–EtOAc; DMF removed
by repeated water–EtOAc extraction for IR (cmꢂ1): 3337, 3191,
3119, 3062, 3003, 2948, 2237 (CN), 1706 (C]O), 1603, 1562,
1536, 1504, 1323, 1180 & 1134 (C–F), 1050, 895, 857, 640, 558; 1H
NMR (300 MHz, 20 mg: 0.4 mL CDCl3): d 2.02 (6H, s, CH3), d 3.53
(br, s, NH), d 8.18 (d, ArH5, J 8), d 8.26 (dd, ArH6, J 2, J 8), d 8.40
(d, ArH2, J 2), d 10.80 (s, NH); 13C NMR (75 MHz, 40 mg: 0.4 mL
CDCl3): d 23.7 (s, C-3A/B), d 92.1 (s, C-2), d 103.8 (s, C-40), d 115.9
(s, CN), d 118.1 (q, C-20, J 5), d 123.0 (q, CF3, J 136), d 123.5
(s, C-60), d 132.5 (q, C-30, J 17), d 136.7 (s, C-50), d 143.5 (s, C-10),
d 167.4 (s, C-1); Neg ESI HRMS: calcd for C12H10N3O3F3 (M ꢂ H):
300.0596, observed: m/z 300.0602.†
IR spectra were measured on a Varian 1000 FTIR spectrom-
eter as KBr disks (4000–400 cmꢂ1) with images provided in the
1
ESI.† H and 13C NMR spectra were recorded on a Bruker 300
MHz spectrometer (images provided in the ESI†). Chemical
shis in 1H NMR spectra were reported in parts per million
(ppm d) relative to the TMS signal and were measured using the
residual chloroform solvent signal set to 7.24 ppm. Chemical
shis in 13C NMR spectra were measured relative to the central
peak of the deuterochloroform signal (d ¼ 77.5 ppm). Coupling
constants were reported in Hz. Low-resolution mass spectra for
monitoring and compound conrmation were carried out on a
Varian CP-3800 GC connected to a Varian Saturn 2200 GC-MS-
MS equipped with a 30 m SGE BPX5 Column and also on a
Micromass Platform II electrospray using MassLynx soware.
High-resolution mass spectra for compounds 1–5 were carried
out at Monash University on an Agilent 6220 accurate mass LC-
TOF system equipped with an Agilent 1200 series HPLC column.
High-resolution mass spectra for compound 6 and RU58841
were carried out at RMIT on a Waters GCT Premier HR-TOFMS
equipped with an Agilent 7890 GC column. Crystallography was
carried out on a Bruker APEX II DUO diffractometer.
2-Amino-N-[4-cyano-3-(triuoromethyl)phenyl]-2-methyl-
propanamide (compound 3)
Compound 2 (5.00 g, 13.4 mmol) was placed in a ask and
solvents were added, namely ethanol (32 mL), water (18 mL) and
2-propanol (9 mL). Fe0 powder (1.50 g, 35.8 mmol) was added
and the reaction taken to reux (90 ꢁC) at which time ꢀ1 mL of
[32%] hydrochloric acid was added through the top of the
condenser. Aer 1 h the reaction was allowed to cool and TLC
showed start material gone, replaced by a tailing spot typical of
an amine.
2-Bromo-N-[4-cyano-3-(triuoromethyl)phenyl]-2-methyl-
propanamide (compound 1)
For the workup it should be noted that 3 is highly soluble in
EtOAc. Another type of hydrogenation may be preferred to
3-Triuoromethyl-4-cyanoaniline (3.00 g, 16.1 mmol) was dis- perform this reaction on large scale. Our workup was as follows:
solved in 1,2-dichloroethane (35 mL) and placed in a ask that reaction mixture was vacuum ltered through celite to remove
contained oven-dried K2CO3 (2.00 g), to keep the mixture iron solids and the celite ushed with hot ethanol. Water–
anhydrous and basic. a-Bromoisobutyryl bromide (4.10 g, ethanol–2-propanol was removed by rotary evaporator and the
17.8 mmol) was added and the mixture stirred at RT for 14 h. solids dissolved in ethyl acetate–water. At pH < 7, compound 3
1,2-Dichloroethane was removed and solids worked up in resides in the aqueous layer. Thus, at the initial pH ꢀ2, the ethyl
EtOAc–water to yield 5.30 g (99%) of 1, which recrystallized from acetate fraction was discarded, removing orange impurities.
hot methanol to give 4.85 g (14.5 mmol) of clear light brown Conc. NaOH was added to the aqueous portion and a dark
cubic crystals, mp 127–129 ꢁC; yield 90%; Rf ¼ 0.50 in 4 : 1 green/black Fe0 precipitate appeared at pH ꢀ5. The precipitate
hexanes–EtOAc; IR (cmꢂ1): 3293, 3099, 3057, 2987, 2935, 2234 was removed by passing the mixture through celite. On addition
(CN), 1666 (C]O), 1586, 1520, 1427, 1325, 1185 & 1139 (C–F), of more NaOH, a white solid (3) precipitated. Ethyl acetate was
1052, 847, 672; 1H NMR (300 MHz, CDCl3): d 2.06 (6H, s, CH3), added to dissolve this and the pH of the aqueous layer was
d 7.82 (d, ArH5, J 8), d 7.92 (dd, ArH6, J 2, J 8), d 8.05 (d, ArH2, brought to ꢀ10. When a little more Fe0 precipitate dried to the
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bottom of the aqueous layer, this fraction and the solid were
drawn off and discarded. The ethyl acetate fraction was then
washed with another volume of deionised water before being
dried with MgSO4 and again ltered through celite. The celite
was rinsed with hot ethyl acetate. The solvent was removed from
the combined ethyl acetate fractions by rotary evaporator to give
2.72 g (10.0 mmol) of 3 as clean white uffy crystals, mp 113–
115 ꢁC; yield 75%; Rf ¼ 0.11 in 1 : 1 hexanes–EtOAc; IR (cmꢂ1):
3388, 3362, 3277 & 3233 (N–H), 2993, 2972, 2934, 2231 (CN),
1699 (C]O), 1613, 1514, 1490, 1422, 1326, 1178 & 1138 (C–F),
N-(1-{[4-Cyano-3-triuoromethyl)phenyl]carbamoyl}-1-
methylethyl-2-methyl-2-nitropropanamide (compound 5)
Compound 4 (1.00 g, 2.38 mmol) was dissolved in DMF (15 mL).
NaNO2 (1.30 g, 18.8 mmol) added and the mixture stirred at RT
for 14 h. The reaction was monitored by TLC and electrospray
mass spectrometry. TLC showed that all compound 4 had
reacted and a single different Rf of the newly formed compound.
High resolution mass spectrometry conrmed the bromine had
been replaced by a nitro group. The product was not isolated
but used in situ for the next step.
1
1050, 909, 888, 858, 749, 734, 673, 558; H NMR (300 MHz, 75
Rf ¼ 0.50 in 1 : 1 hexanes–EtOAc; neg ESI HRMS: calcd for
mg: 0.5 mL DMSOd6): d 1.34 (6H, s, CH3), d 3.53 (br, s, NH),
d 5.05 (br, s, NH), d 8.04 (d, ArH5, J 8), d 8.18 (dd, ArH6, J 2,
J 8), d 8.43 (d, ArH2, J 2); 13C NMR (75 MHz, 75 mg: 0.4 mL
DMSOd6): d 29.2 (s, C-3A/B), d 56.3 (s, C-2), d 102.4 (s, C-40),
d 116.8 (s, CN), d 117.8 (q, C-20, J 5), d 123.1 (s, C-60), d 123.4 (q,
CF3, J 136), d 132.6 (q, C-30, J 17), d 137.2 (s, C-50), d 144.6 (s, C-10),
d 179.1 (s, C-1); Neg ESI HRMS: calcd for C12H12N3OF3 (M ꢂ H):
270.0854, observed: m/z 270.0864.†
C
16H17N4O4F3Br (M ꢂ H): 385.1124, observed: m/z 385.1133.
4-(4,4-Dimethyl-2,5-dioxoimidazolidin-1-yl)-
2-(triuoromethyl)benzonitrile (compound 6)
The reaction vessel from the preparation of 5 was tted with an
air condenser and heated at 110 ꢁC for 7 h,‡ the DMF was then
removed by vacuum and the white solids worked up in water–
ethyl acetate to obtain 587 mg (1.98 mmol) of 6 (83% yield).
Longer reaction time or increased reaction temperature gave 6
in reduced yield that was harder to purify. For the purposes of
obtaining mp, IR and NMR 6 was recrystallized from hot 2-
propanol which lowered the yield to 40%.
2-Bromo-N-(1-{[4-cyano-3-(triuoromethyl)phenyl]carbamoyl}-
1-methylethyl)-2-methylpropanamide (compound 4)
Compound 3 (1.03 g, 3.80 mmol) was dissolved in 1,2-dichlo-
roethane (20 mL) in a ask that contained oven dried K2CO3
(1.00 g) and then stirred with a-bromoisobutyryl bromide
(1.06 g, 4.06 mmol) for 14 h. 1,2-Dichloroethane was removed
and the product worked up in EtOAc–water to yield 1.36 g
(3.23 mmol) of 4 (85% yield) as an oil that solidied to an
amorphous off-white foam aer several hours at high vacuum.
For crystallization, the solid was dissolved in dichloro-
methane and passed through a short column of silica gel,
eluting with ethyl acetate. Aer evaporation of the solvent, the
residue was further puried by extraction with boiling n-
heptane. Aer cooling, the n-heptane was decanted off and the
solid was recrystallized from m-xylene/n-pentane. Crystalliza-
tion was slow and was completed overnight at 8 ꢁC. The
resulting crystals, (mp 121–123 ꢁC) were pure enough for use in
the next step, but contained co-crystallized m-xylene. To remove
this, they were heated to 60 ꢁC for 6 h under high vacuum,
giving a white powder that could be converted to solvent-free
Mp 210–212 ꢁC; yield 83%; UV max ¼ 256 nm (3 ¼ 16200); Rf
¼ 0.25 in 1 : 1 hexanes–EtOAc; IR (cmꢂ1): 3337, 3121, 2983,
2936, 2242 (CN), 1789, 1725 (C]O), 1612 (C]O), 1504, 1440,
1398, 1282, 1182, 1135, 1049, 899, 855, 808, 762, 733, 658, 559,
1
441; H NMR (300 MHz, 20 mg: 0.4 mL CD3CN): d 2.88 (6H, s,
CH3), d 6.85 (s, NH), d 8.62 (dd, ArH6, J 2, J 8), d 8.70 (d, ArH5, J 8),
d 8.75 (d, ArH2, J 2); d 13C NMR (75 MHz, 20 mg: 0.4 mL CD3CN):
d 25.3 (s, CH3 ꢃ 2), d 59.7 (s, hyd-C-5), d 108.8 (s, C-40), d 116.5
(s, CN), d 123.7 (q, CF3, J 136), d 124.9 (q, C-20, J 5), d 130.4
(s, C-60), d 133.4 (q, C-30, J 17), d 137.0 (s, C-50), d 138.2 (s, C-10),
d 154.4 (s, hyd-C-2), d 177.1 (s, hyd-C-4); GC-(EI)TOF-HRMS:
calcd for C13H10N3O2F3 (M): 297.0725, observed: m/z 297.0713.
4-[3-(4-Hydroxybutyl)-4,4-dimethyl-2,5-dioxoimidazolidin-1-yl]-
2-(triuoromethyl)benzonitrile (RU58841)
Anhydrous conditions were kept by oven drying of glassware
and ame drying with a Schlenk line using the vac/purge
method. Compound 6 (1.00 g, 3.37 mmol) was dissolved in dry
DMF (25 mL). NaH 60% suspension in mineral oil (280 mg,
7.00 mmol) was twice washed in a sealed ask with dry n-hexane
(5 mL) using a syringe. The solution of 6 in DMF was then added
to the ask containing the NaH by pressure equalizing funnel.
The two were stirred for 15 min until bubbles of H2 gas ceased.
4-Bromobutyl acetate (680 mg, 3.49 mmol) was then added by
syringe through the addition funnel and washed in with a
second 25 mL portion of dry DMF. The mixture was stirred and
heated at 50 ꢁC for 2 h. A pellet of NaOH (ꢀ200 mg) was added,
followed by deionized water (45 mL).
ꢁ
crystals for crystallography (mp 107–109 C) by very slow evap-
oration from tolꢁuene.
ꢁ
Mp 107–109 C or 121–123 C when co-crystallized with m-
xylene; Rf ¼ 0.78 in 1 : 1 hexanes–EtOAc or 0.07 in 4 : 1 hexanes–
EtOAc; IR (cmꢂ1): 3401, 3312 (N–H), 2992, 2932, 2229 (CN),
1722, 1664 (C]O), 1611 (C]O), 1512, 1427, 1328, 1174 & 1132
1
(C–F), 1049, 882, 850, 555; H NMR (300 MHz, 32 mg: 0.4 mL
DMSOd6): d 1.51 (6H, s, C-3/CH3), d 1.94 (6H, s, C-6/CH3), d 3.38
(NH-2), d 8.09 (d, ArH5, J 8), d 8.15 (dd, ArH6, J 2, J 8), d 8.34 (d,
ArH2, J 2), d 10.03 (NH-1); 13C NMR (75 MHz, 32 mg: 0.4 mL
DMSOd6): d 24.8 (s, C-3A/B), d 31.7 (s, C-5A/B), d 58.2 (s, C-5), d 61.7
(s, C-2), d 102.3 (s, C-40), d 116.8 (s, CN), d 117.8 (q, C-20, J 5),
d 123.2 (s, C-60), d 123.5 (q, CF3, J 136), d 132.4 (q, C-30, J 17),
d 137.3 (s, C-50), d 146.0 (s, C-10), d 171.1 (s, C-4), d 174.7 (s, C-1);
Neg ESI HRMS: calcd for C16H17N3O2F3Br (Mꢂ): 420.0359,
observed: m/z 420.0362.†
‡ It is possible to capture 2-nitropropane as a commercial by-product during this
step as we have observed it on a small scale reactive distillation. However optimal
conditions for simultaneous ring closure and capture of 2-nitropropane have not
yet been developed.
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The crude yield was 92–98% when the DMF and water
was removed by evaporation but for a more pure product the
ask contents were cooled overnight at 0 ꢁC and the solids
collected for an 80% yield of RU58841 (996 mg, 2.70 mmol).
Following instructions from Battmann et al.4 the product
was recrystallized from diisopropyl ether. We found RU58841
hard to dissolve even in a large volume of diisopropyl ether.
The addition of a similar volume of n-heptane as an anti-
Acknowledgements
We acknowledge the School of Applied Sciences and College of
Science, Health & Engineering at RMIT for providing Matthew's
PhD scholarship. We would like to thank Frank Antolasic at
RMIT and Sally Duck at Monash University for help with mass
¨
spectrometry measurements. We also thank Jorg Wagler at
¨
Technische Universitat Bergakademie, Freiberg for assistance
ꢁ
solvent was necessary followed by overnight standing at 8 C
to crystallize.
with crystallography. We acknowledge Jamie Simpson at Monash
Institute of Pharmaceutical Sciences for use of lab space. We
thank Bob McAllister at University of Otago for C,H,N analyses.
Mp 71–72 ꢁC; yield 80%; UV max ¼ 261 nm (3 ¼ 15 100); Rf ¼
0.07 in 1 : 1 hexanes–EtOAc or 0.18 in 1 : 3 hexanes–EtOAc or
0.42 in EtOAc; IR (cmꢂ1): 3392 (OH), 3133, 2944, 2876, 2234
(CN), 1774, 1719 (C]O), 1612 (C]O), 1505, 1438, 1413, 1377,
1312, 1179 & 1133 (C–F), 1051, 894, 837, 763, 675, 555; 1H NMR
(300 MHz, 20 mg: 0.4 mL CDCl3): d 1.52 (6H, s, CH3), d 1.64 (2H,
m, CH2-3), d 1.82 (2H, m, CH2-2), d 2.12 (1H, s, OH), d 3.39 (2H, t,
CH2-1, J 6), d 3.68 (2H, t, CH2-4, J 6), d 7.89 (d, ArH5, J 8), d 7.98
(dd, ArH6, J 2, J 8), d 8.13 (d, ArH2, J 2); d 13C NMR (75 MHz, 20
mg: 0.4 mL CDCl3): d 23.7 (s, CH3 ꢃ 2), d 26.4 (s, al-C-2), d 30.0
(s, al-C-3), d 40.4 (s, al-C-1), d 62.2 (s, hyd-C-5), d 62.3 (s, al-C-4),
d 108.4 (s, C-40), d 115.3 (s, CN), d 122.3 (q, CF3, J 136), d 123.3 (q,
C-20, J 5), d 128.2 (s, C-60), d 133.8 (q, C-30, J 17), d 135.6 (s, C-50),
d 136.8 (s, C-10), d 153.2 (s, hyd-C-2), d 174.9 (s, hyd-C-4); GC-(EI)
TOF-HRMS: calcd for C17H18N3O3F3 (M): 369.1300, observed:
m/z 369.1294.
Notes and references
1 C. Montagne and M. Shipman, Synlett, 2006, 2203–2206.
2 P. Chemla, Tetrahedron Lett., 1993, 34(46), 7391–7394.
3 A. Volonterio and M. Zanda, Tetrahedron Lett., 2003, 44,
8549–8551.
4 T. Battmann, A. Bonls, C. Branche, J. Humbert, F. Goubet,
G. Teutsch and D. Philibert, J. Steroid Biochem. Mol. Biol.,
1994, 48(1), 55–60.
5 D. Cousty-Berlin, B. Bergaud, M. C. Bruyant, T. Battmann,
C. Branche and D. Philibert, J. Steroid Biochem. Mol. Biol.,
1994, 51(1/2), 47–55.
´
6 S. H. Windahl, R. Galien, R. P. Chiusaroli, P. Clement-
Lacroix, F. Morvan, L. N. Lepescheux, F. O. Nique,
W. C. Horne, M. L. Resche-Rigon and R. Baron, J. Clin.
Invest., 2006, 116(9), 2500–2509.
C, H, N: calcd for C17H18N3O3F3: 55.28, 4.91, 11.38. Found:
55.19, 4.84, 11.28.
7 T. Battmann, C. Branche, F. Bouchoux, E. Cerede,
D. Philibert, F. Goubet, G. Teutsch and M. Gaillard-Kelly,
J. Steroid Biochem. Mol. Biol., 1998, 64(1–2), 103–111.
8 B. De Brouweri, C. Tetelini, T. Leroyi, A. Bonls and D. Van
Neste, Br. J. Dermatol., 1997, 35(5), 699–701.
Crystallography
1 (CCDC 894556) was obtained from a single crystal grown in
methanol and shows the correct structure.
2 (CCDC 904089) was obtained aer crystallization in DMF with
9 W. Gao, C. Bohl and J. Dalton, Chem. Rev., 2005, 105, 3352–3370.
¨
the addition of water. The crystal structure revealed a 1 : 1 co- 10 H. M. Hugel, C. J. Rix and K. Fleck, Synlett, 2006, 2290–2292.
crystallization of 2 with DMF.
3 (CCDC 893326) conrmed the structure. The experimental
procedure gave a suitable crystal directly.
11 K. Fleck, PhD thesis, Synthetic approaches to the N-Arylation of
imides, RMIT University, 2005, p. 101.
12 H. Sayo, H. Ohomori, T. Umeda and M. Masui, Bull. Chem.
Soc. Jpn., 1971, 45, 203–208.
4 (CCDC 892388) this single crystal proved difficult to grow and
involved rst co-crystallizing with m-xylene, removal of solvent 13 M. B. Smith and J. March, March's Advanced Organic
ꢁ
under high vacuum at 60 C, then recrystallizing in toluene to
Chemistry: Reactions, Mechanisms, and Structure, John Wiley
give a single crystal for diffractometry.
& Sons, 6th edn, 2007, p. 571, (and references therein).
14148 | RSC Adv., 2014, 4, 14143–14148
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