Observation by NMR of cationic Wheland-like intermediates in the deiodination of protected 1-iodonaphthalene-2,4-diamines in acidic media

Article abstract of DOI:10.1039/c3ob41386a

1-Iodonaphthalene-2,4-diamines in trifluoroacetic acid/chloroform give stable Wheland-like tetrahedral cationic species observable by NMR, through an initial intramolecular protonation. Dynamic equilibria allow proton-deuterium exchange of aromatic protons and provide a mechanism for deiodination of 1-iodonaphthalene-2,4-diamines. The Royal Society of Chemistry.

Full text of DOI:10.1039/c3ob41386a

Organic &
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Observation by NMR of cationic Wheland-like
intermediates in the deiodination of protected
Cite this: Org. Biomol. Chem., 2013, 11,
6208
1-iodonaphthalene-2,4-diamines in acidic media†
Elvis A. Twum,a Timothy J. Woodman,a Wenyi Wanga,b and Michael D. Threadgill*a
Received 5th July 2013,
1-Iodonaphthalene-2,4-diamines in trifluoroacetic acid/chloroform give stable Wheland-like tetrahedral
cationic species observable by NMR, through an initial intramolecular protonation. Dynamic equilibria
allow proton-deuterium exchange of aromatic protons and provide a mechanism for deiodination of
1-iodonaphthalene-2,4-diamines.
Accepted 5th August 2013
DOI: 10.1039/c3ob41386a
www.rsc.org/obc
dichloromethane (Scheme 1). However even prolonged reac-
tion (ca. 7 days, 20 °C) only resulted in the isolation of 10,
Introduction
Cyclopropabenzindoles (CBI) are more biologically potent, from unanticipated loss of iodine but retention of the nor-
stable and synthetically accessible analogues of cyclopropa- mally acid-labile Boc groups. Further attempts with more con-
pyrroloindole (CPI) antitumour antibiotics, such as duocarmy- centrated solutions of CF3CO2H removed both Boc groups but
cin-SA 1 and CC1065 2 (Fig. 1).1,2 These compounds are the iodine was lost, giving 9. To understand the process more
exquisitely potent cytotoxins (1 shows IC50 = 10 pM against fully, a series of NMR-scale experiments was undertaken,
L1210 cells)3 but it is this very potency that makes them difficult leading to identification of unexpected cationic Wheland-like
to develop as selective anticancer drugs. Recently, much effort intermediates.
has gone into developing prodrugs (e.g. 3, 4) for selective deliv-
ery of CPIs and CBIs to tumours.2,4 Efficient routes to the
required hydroxy-seco-CBIs are available but access to the
Results and discussion
corresponding amino-seco-CBIs is more challenging.5,6
Compound 11 was dissolved in deuteriochloroform (150 μL)
and CF3CO2H (450 μL) at 0 °C in a 5 mm NMR tube and intro-
duced to the pre-cooled spectrometer probe. The course of the
As part of our research towards a general route to amino-
seco-CBIs, di-Boc-1-iodonaphthalene-2,4-diamine 11 was pre-
pared from 2,4-dinitronaphthalen-1-ol 6 in five steps, as shown
in Scheme 1. Inexpensive Martius Yellow 6 was triflated at
oxygen, forming 7.5 SNAr displacement of the triflate with
iodide then produced the iodonaphthalene 8 in good yield.
1
reaction was followed by H NMR at 0 °C for 120 min, during
which time both Boc groups were cleaved to give 15 in good
1
yield (>90%, by H NMR) (Scheme 2). Although the NMR spec-
trum of 10 is clear, it was noted that new peaks upfield of the
signals for the aromatic protons of 15 were slowly appearing.
Raising the temperature to 20 °C caused these new signals to
become dominant until, after 2 h at 20 °C, they were present at
Unfortunately, reduction of the nitro groups of
8 was
accompanied by complete loss of the iodine to form the
naphthalenediamine 9, which was converted into the di-Boc-
protected derivative 10. The iodine was restored electrophili-
cally with an I+-equivalent generated from N-iodosuccinimide
and toluenesulfonic acid, affording the key intermediate 11.
For our route, we needed to discriminate between the two
amine nitrogens in 11 to access either 12 or 13 or to form the
diamine 14 (for later selective reprotection) by treatment with
a dilute (0.85%, one equiv.) solution of trifluoroacetic acid in
1
>90%, with loss of the peaks for 15; selected H NMR spectra
from this experiment are shown in Fig. 2. The new compound
was fully assigned through 1-D and 2-D NMR experiments and
was identified as the Wheland intermediate-like tetrahedral
cationic species 16.‡ Most significant is the signal at δ 9.64 in
the 13C spectrum, arising from an sp3 carbon, with an associ-
ated proton signal at δ 6.50, as shown by HSQC. The upfield
‡NMR spectroscopic data for 16. 1H NMR (CDCl3–CF3CO2H, 293 K) δ 6.05 (1 H,
s, 3-H), 6.51 (1 H, s, CHI), 7.58 (1 H, t, J = 7.8 Hz), 7.75 (1 H, d, J = 7.8 Hz), 7.70
(1 H, t, J = 7.8 Hz), 7.84 (1 H, d, J = 8.0 Hz); 13C NMR (CDCl3–CF3CO2D, 293 K) δ
9.79 (CHI), 91.49 (CH), 121.68 (Cq), 124.16 (CH), 129.93 (CH), 131.48 (CH),
135.01 (CH), 141.25 (Cq), 164.30 (CNH3+), 173.50 (CNH3+).
aMedicinal Chemistry, Department of Pharmacy and Pharmacology, University of
Bath, Claverton Down, Bath, BA2 7AY, UK. E-mail: m.d.threadgill@bath.ac.uk
bDepartment of Pharmacy, Shandong University, China
†Electronic supplementary information (ESI)
available. See DOI:
10.1039/c3ob41386a
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Fig. 1 Structures of duocarmycin-SA 1, CC1065 2 and representative prodrugs of CBIs 3–5.
Scheme 1 Syntheses of protected 1-iodo-2,4-dinitronaphthalenes 11 and 26 used in the study and reaction of 11 with CF3CO2H. Reagents: i, Tf2O, Et3N, CH2Cl2; ii,
NaI, acetone, Δ; iii, SnCl2, EtOAc; iv, Boc2O, THF, Δ; v, N-iodosuccinimide, TsOH, THF, MeOH; vi, 0.85% CF3CO2H in CH2Cl2; vii, >5% CF3CO2H in CH2Cl2; viii, (CF3CO)2O,
Pri2NEt, THF.
shift of the aromatic proton can be attributed to the loss of
More information about the reaction was obtained using
aromaticity, the stabilisation of the positive charge in the com- CF3CO2D. The overall course of the reaction was similar, with
pound and the shielding effects of the iodine. 3-H§ also experi- removal of both Boc groups at 0 °C at 2 h and at 20 °C, a tetra-
ences a significant upfield shift of 2.06 ppm. Cation 16 is hedral cationic species again formed. However, both the signal
relatively stable in CF3CO2H–chloroform solution, with little at δ 6.50 (1-H) and the signal at δ 6.05 (3-H) show smaller than
change during 7 d at 20 °C. However, all attempts at isolation expected intensity, as a result of H → D exchange. Interest-
afforded only the de-iodinated product 9.
ingly, this effect is seen even when only small amounts of 18
have been formed. Initially, the signal for 1-H integrates for
0.24 H (i.e. 76% of the 1-H have been replaced with deuter-
ium), whereas 3-H integrates for only 0.10 H. The presence of
D at the 1- and 3-positions was confirmed by the 13C showing
as a triplet owing to 13C–D coupling. Over time, the intensity
§To avoid confusion, all positions on the naphthalene ring are numbered in the
discussion according to the iodonaphthalene educts, with N-containing groups
at 2- and 4-positions.
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Scheme 2 Reactions of 11, 9 and 26 with CF3CO2H and with CF3CO2D in CDCl3, showing intramolecular 1,3-proton shifts to form Wheland-like intermediates 16,
18, 21 and 23 and numbering scheme used throughout. Reagents: i, CF3CO2H–CDCl3 (3 : 1); ii, CF3CO2D–CDCl3 (3 : 1); iii, aq. work-up.
the 1-C is likely to be intramolecular from the N+H2D or the
But cation is the source; if it were intermolecular from the tri-
fluoroacetic acid, then the ratio of H/D in the Wheland-like
species would reflect the overall solution ratio from the start.
Since 3-H displays this ratio at all times, exchange at this posi-
tion is much more rapid and may proceed directly from
solvent. It is likely that the solution contains a mixture of di-
cations and monocations but only the monocations have
sufficient electron density to react (thus only the reactive
monocations are shown in Scheme 2).
Similar experiments were undertaken with 9, with CF3CO2H
and with CF3CO2D (Scheme 2). Treatment of 9 with CF3CO2H–
deuteriochloroform at 20 °C afforded a mixture of two com-
pounds, assigned as the di-protonated naphthalenediamine
20 and a tetrahedral species 21, in ratio ca. 4 : 1, as shown
by NMR. Of particular note is the presence of a CH2 in 21,
confirmed by a phase-sensitive HSQC spectrum with a corre-
Fig. 2 Time-course of 1H NMR spectra of reaction of 11 with CF3CO2H–CDCl3
lation peak at δ 4.13 in 1H and δ 33.27 in 13C. As with the iodo-
(3 : 1).
compound 11, the aromatic protons show a marked up-field
shift in moving to the cationic Wheland species. There was
little or no change in the ratio 20 : 21 in CF3CO2H during 7 d
of the 1-H signal decreased further; ultimately the ratio of the at 20 °C. When the experiment was repeated with CF3CO2D,
signals for the aromatic protons to these signals is close to deuterium was found to wash into both the 1- and 3-positions
10 : 1, which reflects of the overall ratio of exchangeable D to H of 23 and, significantly, into the 1- and 3-positions of 22. This
in solution. The presence of a larger signal for protium at 1-H provides confirmation that 22 and 23 are in equilibrium. Sur-
than for the overall ratio in solution at early time points pro- prisingly, the initial spectral data for 23 showed that the signal
vides mechanistic information. Addition of a deuteron to 2-N for 1-H integrates to almost two protons relative to the other
is rapid but H/D exchange at this nitrogen is slow, so that full aromatic protons and thus has very little deuterium incorpor-
equilibration of H and D is not complete in the time taken to ated when first formed. As with the formation of 16/18, this
obtain the first NMR data. It follows that the protonation at gives strong evidence for an intramolecular mechanism of
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protonation at 1-C, as the But cation is absent from this reac-
tion mixture. After 48 h, this signal had reduced in size and a
new triplet, slightly upfield at δ 4.14, arose. This peak corre-
lated with a signal for a carbon with one proton attached
(from the DEPT135 spectrum) and is assigned as CHD. The
signal for 3-H also diminishes rapidly as deuterium was incor-
porated; at 4 min, the 3-H signal integrated for 0.18 H,
whereas 1-H integrated for 1.0 H. Exchange at 3-H is much
more rapid than for 1-H. Incorporation of D has a marked
effect on the 13C signals for 1-C and 3-C.
To explore the effect of a non-acid-labile amide group at N3,
the N1-Boc-N3-TFA differentially protected naphthalened-
iamine 26 was prepared (Scheme 1). Treatment of 9 with
stoichiometric trifluoroacetic anhydride in dilute solution in
THF achieved selective protection of the less-hindered amine
in 15% yield. Interestingly, Hawkins et al.7 reported selective
introduction of Boc at this position with Boc-ON but in only
8% yield of crude material. Masking the remaining amine with
Boc and introduction of the iodine gave 26. With trifluoro-
acetamide adjacent to the iodine, treatment of 26 with
CF3CO2H in deuteriochloroform did not lead to NMR-observa-
ble concentrations of any tetrahedral cation. Following loss of
Boc, only 27 was observed and, after 48 h, iodine was lost to
afford 28, shown by the presence of a signal at δ 8.29 for 1-H.
Significantly, when CF3CO2D was used, both this peak and 3-H
showed a reduced intensity after 48 h, indicating that deuter-
ium is incorporated. A transient Wheland cationic species may
be involved but the equilibrium concentration is too low for
observation. Deuterium was also incorporated into 29/30.
In each case where Boc was lost, the NMR spectra showed that
the tert-butyl was trapped by solvent as tert-butyl trifluoroacetate.
With CF3CO2D, deuterium was incorporated, giving clearly
identifiable F3CCO2C(CH3)(CH3)(CH2D), F3CCO2C(CH3)(CH2D)-
(CH2D) and F3CCO2C(CH3)(CH3)(CHD2) species, showing that
2-methylpropene is an intermediate.
Fig. 3 Space-filling representations of MM2-minimised structures of 15 and
16, showing relief of steric crowding on moving to tetrahedral sp3 1-C in 16.
show Wheland-like structures from protonation of benzene-
1,3,5-triamine.14
We believe that this is the first direct observation by NMR
of Wheland-like intermediates derived from naphthalenes;
these cations are remarkably stable, even at room temperature,
but decompose on attempted isolation. The formation of these
stable carbocationic species provides a partial explanation for
the unexpected loss of iodine in attempts to cleave Boc groups
from 6. The iodine must be lost from the cationic species as
an electrophilic I+-equivalent. Presumably, the trapping
nucleophile is trifluoroacetate, although, at very long time-
points (>7 d), the solutions turn dark red, suggesting the pres-
ence of I2.
The abundant tetrahedral Wheland-like species 16/18,
observed by NMR, is stabilised both by delocalisation of
charge (including with the nitrogens) and by relief of steric
compression between the very large iodine (R = 1.98 Å) and the
peri 8-H as it moves from the sp2-hybridised educt to the sp3-
hybridised 1-C in the cation. However, the presence of iodine
in the molecule is not essential for the formation of these cat-
ionic species, as shown by the formation of 21/23 and the reac-
tions of 27/29. Fig. 3 shows space-filling representations of
MM2-minimised structures of 15 and 16, to illustrate this
point.
Electrophilic aromatic substitution proceeds via an initial
π-complex, which converts to a “σ-complex”; the latter is better
recognised as the covalent Wheland intermediate. Several
σ-complexes have been identified by their charge-transfer UV-
vis absorptions and by crystallography.8 The vast majority of
Wheland intermediates are extremely transient, owing to rapid
deprotonation, only being observed by fs time-resolved laser
absorption spectroscopy. A few examples have sufficient life-
time to be characterised by NMR. 1,3,5-Trimethylbenzene and
Conclusions
+
−
hexamethylbenzene react with NO2 BF4 in super-acid media
at −70 °C to give NMR-observable Wheland intermediates but Here we report the generation of Wheland-like intermediates
these decompose on warming.9 Wheland intermediates have from (Boc-protected) naphthalenediamines. When the adja-
been isolated with carboranyl counter-anions (characterised by cent amine lacks an electron-withdrawing carbonyl, these
NMR at low temperature)10 and where the molecule contains intermediates are present in high concentrations in trifluoro-
1
both Wheland-like cations and Meisenheimer-like anions.11 acetic acid, characterisable by H and 13C NMR at 0 °C and at
The formation of Wheland intermediates from 1,3,5-tris(di- 20 °C, much higher than have been used previously for less-
alkylamino)benzenes under acidic conditions has been stabilised benzenium cations. Strikingly, the source of the
studied and reviewed by Effenberger.12 Wheland intermediate proton at the new tetrahedral carbon is shown to be intramole-
cations have also been observed by NMR in azo-coupling reac- cular, through a 1,3-proton shift. These studies provide evi-
tions of these molecules with arenediazonium salts.13 UV spec- dence for the mechanism of protio-deiodination of ortho-
troscopy and thermochemical studies have been reported to iodoanilines and ortho-iodoanilides.
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Naphthalene-1,3-diamine (9)
Experimental
Compound 8 (1.05 g, 2.9 mmol) and tin(II) chloride dihydrate
(9.84 g, 44 mmol) in ethyl acetate (100 mL) were heated under
reflux for 17 h. The mixture was added to ice and sodium
hydrogen carbonate was added until the aqueous layer was
basic. The mixture was extracted with ethyl acetate and the
combined extracts were washed with water and dried. Evapor-
ation gave crude 9 as a dark brown solid: δH (CDCl3) 3.71 (2 H,
s, NH2), 4.08 (2 H, s, NH2), 6.23 (1 H, d, J 2.1 Hz, 2-H), 6.50
(1 H, d, J 1.9 Hz, 4-H), 7.18 (1 H, ddd, J 8.2, 6.8, 1.2 Hz, 7-H),
7.34 (1 H, ddd, J 8.0, 6.8, 1.0 Hz, 6-H), 7.53 (1 H, d, J 8.2 Hz,
5-H), 7.64 (1 H, d, J 8.4 Hz, 8-H); δH (CDCl3) 100.67 (4-C), 100.58
(2-C), 118.65 (8a-C), 120.67 (8-C), 121.36 (7-C), 126.39 and
126.42 (5-C and 6-C), 136.01 (4a-C), 143.28 (1-C), 144.71 (3-C).
NMR experiments were performed using a Bruker Avance III
spectrometer operating at 500.13 MHz (1H), 125.77 MHz (13C)
and 470.52 MHz (19F). The residual solvent peak was used as
1
an internal reference for H (δ = 7.26 ppm for CDCl3) and 13C
(δ = 77.0 ppm) and 19F was referenced externally to BF3·OEt2
(δ = −132.0 ppm). Mass spectrometry was carried out on a
micrOTOF™ from Bruker Daltonics (Bremen, Germany) using
an electrospray source (ESI-TOF). Melting points were obtained
using a Reichert-Jung heated-stage microscope. IR spectra were
recorded on a Perkin-Elmer 782 infra-red spectrometer using
potassium bromide discs. TLC was carried out on Merck
aluminium-backed TLC plates Silicagel 60 F254 and viewed
using UV light (λ = 254 nm). Experiments were conducted at
ambient temperature, unless otherwise noted. Solvents were
evaporated under reduced pressure. Solutions in organic sol-
vents were dried with magnesium sulfate. All reagents and sol-
vents were of commercial reagent grade and were used without
further purification. The brine was saturated.
N,N′-Bis(tert-butoxycarbonyl)naphthalene-1,3-diamine (10)
The above crude 9 was heated under reflux with di-tert-butyl
dicarbonate (3.11 g, 14.2 mmol) in tetrahydrofuran (30 mL) for
17 h. Evaporation and chromatography (dichloromethane)
gave 10 (769 mg, 74%) as a pale buff solid: mp 127–130 °C
(lit.5 mp 129–131 °C); νmax 3254 (NH), 1716 (CvO), 1685
(CvO); δH (CDCl3) 1.54 (9 H, s, But), 1.56 (9 H, s, But), 6.63
(1 H, s, NH), 6.91 (1 H, s, NH), 7.34 (1 H, ddd, J 8.1, 6.8,
1.3 Hz, 6-H), 7.44 (1 H, ddd, J 7.9, 6.9, 1.1 Hz, 7-H), 7.73 (1 H, d,
J 8.2 Hz, 5-H), 7.77 (2 H, m, 1,8-H2), 7.93 (1 H, s, 3-H); δC
(CDCl3) 28.37 (2 × CMe3), 80.63 (CMe3), 80.92 (CMe3), 110.65
(3,8-C2), 119.69 (5-C), 122.5 (4a-C), 124.41 (6-C), 126.49 (7-C),
128.52 (1-C), 133.76 (4-C), 134.82 (8a-C), 135.81 (2-C), 152.76
(CvO), 153.13 (CvO).
2,4-Dinitronaphthalen-1-yl trifluoromethanesulfonate (7)
Martius Yellow (2,4-dinitronaphthalen-1-ol)
6
(501 mg,
2.14 mmol) and triethylamine (562 mg, 5.6 mmol) in dichloro-
methane (10 mL) were cooled in an ice bath and treated drop-
wise with trifluoromethanesulfonic anhydride (784 mg,
2.8 mmol). The mixture was stirred at 20 °C for 2 h under
nitrogen. Aq. hydrochloric acid (0.5 M, 10 mL) was added in one
portion and the mixture was stirred for 30 min. The aqueous
phase was separated and extracted with dichloromethane. The
combined organic phases were washed with sat. aq. sodium
hydrogen carbonate and brine. Drying, evaporation and
chromatography (dichloromethane) gave 7 (484 mg, 62%) as a
yellow solid: mp 117–119 °C (lit.5 mp 105–107 °C); νmax 1532
(NO2), 1365 (–SO2–O–), 1349 (NO2); δH ((CD3)2SO) 7.72 (1 H,
ddd, J 8.2, 7.1, 1.0 Hz, 7-H), 7.91 (1 H, ddd, J 8.4, 7.0, 1.4 Hz,
6-H), 8.51 (1 H, d, J 8.4 Hz, 8-H), 8.57 (1 H, d, J 8.6 Hz, 5-H),
8.87 (1 H, s, 3-H); δC ((CD3)2SO) 120.65 (q, J 322.3 Hz, CF3),
122.31 (3-C), 123.32 (5-C), 125.58 (8-C), 127.49 (2-C), 127.76
(8a-C, 7-C), 128.00 (4a-C), 133.09 (6-C), 134.75 (4-C), 158.70
(1-C); δF (CDCl3) −71.85 (s, CF3).
N,N′-Bis(tert-butoxycarbonyl)-1-iodonaphthalene-2,4-diamine
(11)
Compound 10 (417 mg, 1.28 mmol) was treated with N-iodo-
succinimide (431 mg, 1.9 mmol) and 4-methylbenzenesulfonic
acid hydrate (457 mg, 2.4 mmol) in tetrahydrofuran (7 mL)
and methanol (7 mL) at −78 °C. The mixture was allowed to
warm slowly to 20 °C over 4 h and was then diluted with aq.
sodium thiosulfate (5%) and stirred at 20 °C for 15 min. The
mixture was extracted with ethyl acetate. The combined
organic extracts were dried and the solvents were evaporated.
Chromatography (dichloromethane) gave 11 (400 mg, 71%) as
a pale buff solid: mp 166–168 °C (lit.5 mp 154–156 °C);
νmax 3384 (NH), 3229 (NH), 1733 (CvO), 1683 (CvO); δH
(CDCl3) δ 1.55 (9 H, s, But), 1.57 (9 H, s, But), 6.86 (1 H, s,
4-NH), 7.17 (1 H, s, 2-NH), 7.43 (1 H, dd, J 8.0, 6.9 Hz, 6-H),
7.51 (1 H, dd, J 7.9, 1.1 Hz, 7-H), 7.76 (1 H, d, J 8.2 Hz, 5-H),
8.09 (1 H, d, J 8.4 Hz, 8-H); δC (CDCl3) 28.38 (2 × CMe3), 81.03
(CMe3), 81.28 (CMe3), 87.36 (1-C), 113.71 (3-C), 121.40 (5-C),
124.88 (4a-C), 125.32 (6-C), 128.15 (7-C), 132.58 (8-C), 134.65
(4-C or 8a-C), 134.82 (8a-C or 4-C), 138.22 (2-C), 152.68 (CvO),
153.21 (CvO).
1-Iodo-2,4-dinitronaphthalene (8)
Compound 7 (4.28 g, 11.7 mmol) was heated under reflux with
sodium iodide (5.99 g, 40 mmol) in acetone (170 mL) for 2 h.
The evaporation residue, in ethyl acetate, was washed with sat.
aq. sodium thiosulfate and dried. Evaporation and chromato-
graphy (dichloromethane) gave 8 (2.98 g, 74%) as a yellow
solid: mp 183–186 °C (lit.5 mp 194–195 °C); νmax 1530 (NO2),
1333 (NO2); δH ((CD3)2SO) 7.98 (2 H, m, 6,7-H2), 8.32 (1 H, dd,
J 7.1, 1.7 Hz, 5-H), 8.52 (1 H, dd, J 7.7, 2.0 Hz, 8-H), 8.73 (1 H,
s, 3-H); δC ((CD3)2SO) 102.55 (1-C), 117.53 (3-C), 123.35 (5-C),
N-(1-Aminonaphthalen-3-yl)-2,2,2-trifluoroacetamide (24)
124.01 (4a-C), 131.39 (6-C), 132.32 (7-C), 135.07 (8-C), 135.12 Naphthalene-1,3-diamine 9 (1.29 g, 8.16 mmol) was stirred
(8a-C), 147.21 (4-C), 151.91 (2-C).
in dry tetrahydrofuran (100 mL) under nitrogen at 0 °C.
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N,N-Diisopropylethylamine (4.23 g, 32.6 mmol) was added, fol- δC (CDCl3) 28.31 (CMe3), 81.63 (CMe3), 89.87 (1-C), 113.26 (3-
lowed by dropwise addition of trifluoroacetic anhydride C), 115.77 (q, J 289.3 Hz, CF3), 121.09 (8-C), 125.43 (8a-C),
(1.71 g, 8.16 mmol) in dry tetrahydrofuran (100 mL) during 126.86 (7-C), 128.73 (6-C), 133.17 (5-C), 134.52 (4a-C), 134.90
2 h. The mixture was allowed to warm slowly to 20 °C during (4-C), 135.20 (2-C), 152.82 (Boc CvO), 155.05 (q, J 38.0 Hz,
16 h. The evaporation residue, in ethyl acetate, was washed CF3CvO); δF ((CD3)2SO) −74.13 (s, CF3); m/z (ES+) 503.0100 (M
with water and brine. Drying, evaporation and chromatography + Na) (C17H16F3IN2NaO3 requires 503.0055), 498.0542 (M +
(petroleum ether–ethyl acetate 9 : 1 → 1 : 1) gave 24 (309 mg, +NH4) (C17H20F3IN3O3 requires 498.0500).
15%) as a buff solid: mp 168–169 °C; νmax 3482, 3374, 3324
(NH), 1721, 1706 (CvO); δH (CDCl3) 5.99 (2 H, s, NH2), 7.01
(1 H, d, J 2.0 Hz, 2-H), 7.39 (1 H, ddd, J 8.2, 6.8, 1.3 Hz, 7-H),
7.47 (1 H, ddd, J 8.1, 6.8, 1.2 Hz, 6-H), 7.49 (1 H, d, J 1.4 Hz,
Notes and references
4-H), 7.75 (1 H, d, J 7.7 Hz, 5-H), 8.10 (1 H, d, J 8.4 Hz, 8-H),
11.17 (1 H, s, NH); δC (CDCl3) 101.31 (2-C), 106.51 (4-C), 115.88
(q, J 289.0 Hz, CF3), 120.89 (8a-C), 122.24 (8-C), 123.46 (7-C),
126.34 (6-C), 127.78 (5-C), 134.09 (4a-C), 134.67 (3-C), 145.56
(1-C), 154.41 (q, J 36.6 Hz, CvO); δF ((CD3)2SO) −73.69 (s, CF3);
1 D. L. Boger and D. S. Johnson, Proc. Natl. Acad. Sci. U. S. A.,
1995, 92, 3642; D. L. Boger, C. Boyce, R. Garbaccio,
M. Searcey and Q. Jin, Synthesis, 1999, 1505.
2 L. F. Tietze, M. Müller, S.-C. Duefert, K. Schmuck and
I. Schuberth, Chem.–Eur. J., 2013, 19, 1726; L. F. Tietze,
J. M. von Hof, M. Müller, B. Krewer and I. Schuberth,
Angew. Chem., Int. Ed., 2010, 49, 7336.
m/z (ES+) 277.0554 (M
+ Na) (C12H9F3N2NaO requires
277.0565).
3 M. Ichimura, T. Ogawa, K. Takahashi, E. Kobayashi,
I. Kawamoto, T. Yasuzawa, I. Takahashi and H. Nakano,
J. Antibiot., 1990, 43, 1037.
tert-Butyl N-(3-trifluoroacetamidonaphthalen-1-yl)carbamate
(25)
Compound 24 (330 mg, 1.30 mmol) was boiled under reflux
with di-tert-butyl dicarbonate (1.43 g, 6.55 mmol) in dry tetra-
hydrofuran (10 mL) under nitrogen for 16 h. Evaporation and
chromatography (petroleum ether → petroleum ether–ethyl
acetate 19 : 1) gave 25 (381 mg, 83%) as a pale buff solid. mp
206–208 °C; νmax 3297 (NH), 3244 (NH), 1711 (CvO), 1683
(CvO); δH ((CD3)2SO) 1.57 (9 H, s, But), 7.54 (1 H, td, J 8.2, 1.4
Hz, 7-H), 7.58 (1 H, td, J 8.0, 1.2 Hz, 6-H), 7.94 (1 H, d, J 8.1
Hz, 5-H), 8.00 (1 H, d, J 2.0 Hz, 2-H), 8.13 (1 H, d, J 8.2 Hz,
8-H), 8.20 (1 H, d, J 1.8 Hz, 4-H), 9.39 (1 H, s, NHBoc), 11.50
(1 H, s, NHCOCF3); δC ((CD3)2SO) 28.13 (CMe3), 79.26 (CMe3),
114.63 (2-C), 114.73 (4-C), 115.79 (q, J 288.8 Hz, CF3), 122.64
(8-C), 125.27 (8a-C), 125.33 (7-C), 126.75 (6-C), 128.03 (5-C),
133.52 (4a-C), 133.56 (3-C), 134.92 (1-C), 153.76 (Boc CvO),
154.68 (q, J 37.1 Hz, CF3CvO); δF ((CD3)2SO) −73.76 (s, CF3);
4 M. P. Hay, B. M. Sykes, W. A. Denny and W. R. Wilson,
Bioorg. Med. Chem. Lett., 1999, 9, 2237; L. F. Tietze,
F. Major, I. Schuberth, D. A. Spiegl, B. Krewer,
K. Maksimenka, G. Bringmann and J. Magull, Chem.–Eur.
J., 2007, 13, 4396; R. J. Stevenson, W. A. Denny,
A. Ashoorzadeh, F. B. Pruijn, W. F. van Leeuwen and
M. Tercel, Bioorg. Med. Chem., 2011, 19, 5989;
R. J. Stevenson, W. A. Denny, M. Tercel, F. B. Pruijn and
A. Ashoorzadeh, J. Med. Chem., 2012, 55, 2780; K.-C. Chen,
K. Schmuck, L. F. Tietze and S. R. Roffler, Mol. Pharma-
ceutics, 2013, 10, 1773; M. Sutherland, J. H. Gill,
P. M. Loadman, J. P. Laye, H. M. Sheldrake,
N. A. Illingworth, M. N. Alandas, P. A. Cooper, M. Searcey,
K. Pors, S. D. Shnyder and L. H. Patterson, Mol. Cancer
Ther., 2013, 12, 27.
5 S. Yang and W. A. Denny, J. Org. Chem., 2002, 67, 8958.
6 M. Tercel, G. J. Atwell, S. Yang, A. Ashoorzadeh,
R. J. Stevenson, K. J. Botting, Y. Gu, S. Y. Mehta,
W. A. Denny, W. R. Wilson and F. B. Pruijn, Angew. Chem.,
Int. Ed., 2011, 50, 2606; A. Ashoorzadeh, G. J. Atwell,
F. B. Pruijn, W. R. Wilson, M. Tercel, W. A. Denny and
R. J. Stevenson, Bioorg. Med. Chem., 2011, 19, 4851;
M. P. Hay, R. F. Anderson, D. M. Ferry, W. R. Wilson and
W. A. Denny, J. Med. Chem., 2003, 46, 553.
m/z (ES+) 377.1120 (M
+
Na) (C17H17F3N2NaO3 requires
377.1089).
tert-Butyl N-(1-iodo-2-(trifluoroacetamido)naphthalen-4-yl)-
carbamate (26)
Compound 25 (336 mg, 0.95 mmol) in dry tetrahydrofuran
(10 mL) was cooled to −78 °C and stirred under nitrogen. N-Iodo-
succinimide (309 mg, 1.4 mmol) in dry tetrahydrofuran
(2.0 mL) was added followed by 4-methylbenzenesulfonic acid
hydrate (370 mg, 1.9 mmol) in dry tetrahydrofuran (2.0 mL).
The temperature of the mixture was allowed to rise slowly to
20 °C during 20 h. The reaction was quenched by addition of
sat. aq. sodium hydrogen carbonate. The mixture was diluted
with water and extracted with ethyl acetate. Drying, evapor-
ation and chromatography (petroleum ether → petroleum
ether–ethyl acetate 4 : 1) gave 26 (344 mg, 75%) as a pale buff
7 M. J. Hawkins, M. N. Greco, E. Powell, L. De Garvilla and
B. E. Maryanoff, Patent WO 2005/073214.
8 F. A. Houle and J. L. Beauchamp, J. Am. Chem. Soc., 1979,
101, 4067.
9 R. Rathore and J. K. Kochi, Adv. Phys. Org. Chem., 2000, 35,
193; M. Mascal, J. Hansen, A. J. Blakeand and W.-S. Li,
Chem. Commun., 1998, 35.
solid: mp 198–199 °C; νmax 3323, 3209 (NH), 1721 (CvO), 1698 10 G. A. Olah, H. C. Lin and Y. K. Mo, J. Am. Chem. Soc., 1972,
(CvO); δH (CDCl3) δ 1.57 (9 H, s, But), 6.95 (1 H, s, NHBoc),
7.54–7.61 (2 H, m, 6,7-H2), 7.82 (1 H, d, J 8.1 Hz, 5-H), 8.14 (1
H, d, J 8.6 Hz, 8-H), 8.58 (1 H, s, NHCOCF3), 8.71 (1 H, s, 3-H);
94, 3667; C. A. Reed, N. L. P. Fackler, K.-C. Kim, D. Stasko
and D. D. Evans, J. Am. Chem. Soc., 1999, 121, 6314;
C. A. Reed, K.-C. Kim, E. S. Stoyanov, D. Stasko, F. S. Tham,
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6214 | Org. Biomol. Chem., 2013, 11, 6208–6214
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