2-(3-Pyrrolin-1-yl)-1,4-naphthoquinones: Photoactivated alkylating agents

Article abstract of DOI:10.1002/ejoc.200800482

The preparation of 2-(3-pyrrolin-1-yl)-1,4-naphthoquinones and a study of their use as photoactivated alkylating agents is reported. The title compounds were easily synthesized by conjugate addition of the corresponding 3-pyrrolines to various naphthoquin

Full text of DOI:10.1002/ejoc.200800482

FULL PAPER
DOI: 10.1002/ejoc.200800482
2-(3-Pyrrolin-1-yl)-1,4-naphthoquinones: Photoactivated Alkylating Agents
Aaron Aponick,*[a][‡] Amber L. Dietz,[a] and William H. Pearson[a][‡‡]
Keywords: Quinones / Pyrroline / Michael addition / Alkylation / Photoactivation
The preparation of 2-(3-pyrrolin-1-yl)-1,4-naphthoquinones
and a study of their use as photoactivated alkylating agents
is reported. The title compounds were easily synthesized by
nucleophilic addition by an SN1 azafulvene mechanism. Con-
trol experiments demonstrated that the redox reaction is trig-
gered by light and that the nucleophilic addition does not
conjugate addition of the corresponding 3-pyrrolines to vari- proceed before this activation occurs.
ous naphthoquinones. Upon exposure to ambient room light,
the compounds undergo an internal redox reaction to form
2-(pyrrol-1-yl)-1,4-hydroquinones, which are activated for
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2008)
synthetic molecules that share the reactive pyrrole core of
2, generically represented by 4, have been shown to cross-
link DNA.[4] Unfortunately, these compounds (both syn-
thetic and natural) often prove to be too reactive as they
have the potential to alkylate a multitude of different chemi-
cal species.
Introduction
Many cancer chemotherapy strategies involve drugs that
approach the toxicity level to be effective. Because cancer-
ous cells proliferate more rapidly than normal cells, one ge-
neral chemotherapeutic strategy is to stop the cell-division
process by targeting DNA. During cell division, a DNA
polymerase reads one strand, which it has separated from
the double helix, then synthesizes its complement by relying
on Watson–Crick base pairing of an incoming nucleotide
triphosphate. Thus, if the two strands cannot be separated,
replication is not possible. Reagents that react with DNA
have been shown to form both inter- and intrastrand cross-
links as well as interhelix cross-links and DNA–protein
cross-links.[1] In general, interstrand cross-links are thought
to be the most effective in disrupting this process.
An example of a natural product that cross-links DNA is
illustrated in Scheme 1. Moncrotaline (1) is a carcinogenic
pyrrolizidine alkaloid isolated from plant material in the
pyrroline oxidation state.[2] Upon oxidation by P450 en-
zymes, the highly reactive pyrrole 2 is formed.[3] This species
is the active cross-linker and after two elimination/addition
sequences forms the ultimate adduct 3. In addition to pyr-
rolizidine alkaloids like monocrotoline, other naturally oc-
curring molecules such as mitomycin C metabolites and
Scheme 1. DNA cross-linking by monocrotaline. LG = leaving
group.
Toxicity also plagues these compounds because there is
no specificity for tumor cells over healthy cells. Anderson,
Hopkins, and several other groups, have tried to circumvent
the problems of reactivity and stability in water by synthe-
sizing various analogs, but this has met with only limited
success.[5]
To solve these issues, nature has built in a control ele-
ment with the P450 enzyme activation of monocrotaline (1)
to activate the C-7 and C-9 positions. Chemists have also
added their own control elements by modifying natural
products to contain groups such as photolabile protecting
[a] Department of Chemistry, University of Michigan,
Ann Arbor, MI 48109-1055, USA
[‡] Current address: Department of Chemistry, University of
Florida,
Gainesville, FL 32611, USA
Fax: +1-352-846-0296
E-mail: aponick@chem.ufl.edu
[‡‡]Current address: Berry & Associates, Inc.,
2434 Bishop Circle East, Dexter, MI 48130, USA
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
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2-(3-Pyrrolin-1-yl)-1,4-naphthoquinones: Photoactivated Alkylating Agents
groups that activate the molecule by deprotection of a reac-
tive functional group. Two elegant examples of this have
been reported by Williams in which reactive analogues of
the natural products monocrotaline[6] and FR900482[7] are
released after deprotection of a 6-nitroveratryl carbamate
(NVOC). This concept retains the natural product-like
structure that is responsible for the selective reaction with
DNA, but is limited due to the necessity of a natural prod-
uct starting material. An ideal molecule would be both se-
lective and easily prepared so that the binding could be
modified to select target different sequences.
We sought to combine the idea of a reactive pyrrole such
as 4 with the notion of a triggering event (e.g., light) that
would lead to its generation from a stable starting material.
A search of the literature for the photochemical generation
of pyrroles revealed several interesting examples.[8] Maruy-
ama reported that irradiation of a benzene solution of the
quinone 5 with a mercury arc lamp produced the hydroqui-
none 6 (Scheme 2).[8a] An internal redox reaction provided
the hydroquinone with concomitant oxidation of the pyrro-
line moiety to the pyrrole as evidenced by trapping 6 as the
diacetate in degassed solutions. In experiments where the
solvent was not degassed, the hydroquinone 6 was oxidized
to a pyrrole-bearing quinone. Franck reported the pro-
duction of a pyrrole-bearing quinone from a benzoquinone
and a 3-pyrroline, though the potential role of ambient light
was not noted.[8c]
Figure 1. General design of potential photochemically triggered al-
kylating agents.
Results and Discussion
To prepare the target compounds, a variety of 3-pyrro-
lines (e.g., 8–15) was necessary in order to find the best
choices for the leaving group and its position on the ring
for successful photochemically triggered alkylation chemis-
try. We examined both mono- and bis(alkylators) (Fig-
ure 2).
Figure 2. Desired substituted 3-pyrrolines.
The 3-substituted pyrrolines were prepared by a ring-
closing metathesis (RCM) strategy (Scheme 3).[10] The nec-
essary dienes were prepared in a straightforward manner
starting with alkylation of N-Boc-allylamine (16) with com-
mercially available 3-chloro-2-(chloromethyl)-1-propene
(17). The chloride was then displaced with acetate in 89%
yield, and both 18 and 19 were cyclized in good yield by
using Grubbs’ first-generation catalyst[10] without incident.
Scheme 2. Internal redox reactions of pyrroline-substituted qui-
nones.
With evidence for a photochemically generated pyrrole,
we surmised that the quinones 7, with structures similar to
5 except now bearing one or more leaving groups (LG),
could provide a platform to explore the preparation of sim-
plified alkylating agents. Recent advances in the use of fiber
optics and lasers in medicine[9] make photochemically acti-
vated alkylating agents attractive targets because they can
be introduced in an inactive form and “turned on” at will.
The quinones 7 should not be good alkylating agents until
the photochemical redox reaction takes place to afford the
pyrroles 4. At this point, the deactivating quinone nucleus
has been reduced to an electron-rich hydroquinone, and the
pyrroline ring has been oxidized to a pyrrole, making the
substitution reactions facile by the intervention of azaful-
vene intermediates. In addition, the quinones 7 should be
easily prepared by conjugate addition of the requisite 3-
pyrroline to a quinone (Figure 1). This disconnection
should lead to a facile assembly of a diverse array of com-
pounds with varied 3-pyrroline and quinone fragments. Our
Scheme 3. Synthesis of 3-substituted-3-pyrrolines by RCM.
To prepare the 2-substituted 3-pyrroline 12, the pro-
initial studies to explore the preparation and reactivity of cedure of Blechert was applied to give 11[11] starting with
this potential scaffold are reported herein.
the known N-protected vinylglycine 20[12] (Scheme 4). Re-
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A. Aponick, A. L. Dietz, W. H. Pearson
FULL PAPER
duction of the methyl ester 20 and formation of the oxazoli-
dinone 22 proceeded in good yield. Hydrolysis and Boc pro-
tection then gave the necessary diene 23 in 82% yield. RCM
by using Grubbs’ first-generation ruthenium catalyst pro-
vided 11 and 12 after acylation.
Scheme 6. Synthesis of 2-substituted-3-pyrrolines 14 and 15.
With the 3-pyrrolines in hand we next set out to prepare
a variety of the target quinones represented by the generic
structure 7. Deprotection of the N-Boc groups of the pyrro-
lines and in situ neutralization of the TFA salts followed
by addition of the desired quinone and CuBr proceeded
in reasonable yield (Table 1).[14] This reaction was used to
prepare the naphthoquinones 34–41, juglones 42–43, iso-
quinolinequinones 44–45, and the quinolinequinones 46–
50. It is important to note that these reactions were carried
out in the absence of light to avoid unwanted redox reac-
tions as the preparation of quinone 5 (Scheme 2) in our
laboratories showed that the photochemical reaction pro-
ceeds in ambient room light and that the mercury arc lamp
reported is unnecessary.
Scheme 4. Synthesis of 2-substituted-3-pyrrolines 11 and 12.
The necessary disubstituted analogs were prepared in the
following manner. N-Boc-vinylglycinol, derived from 21,
was protected as its triisopropylsilyl ether (Scheme 5). The
second allyl unit was then introduced by alkylation with the
allyl chloride 17, and the TIPS group was removed with
TBAF in THF, all in good yield. RCM with Grubbs’ second
generation catalyst[10] provided 28 in 98% yield and acyl-
ation provided the desired 3-pyrroline 13.
With a good indication that the photochemical redox re-
action would proceed (vide supra), the next goal was to
optimize the redox reaction and determine if the desired
alkylation was possible. To this end, initial NMR-tube ex-
periments were conducted in CDCl3 as outlined in
Scheme 7. It is desirable to avoid the use of a mercury arc
lamp to trigger the redox reaction because it would be more
convenient to use a sunlamp, but this would also provide
less intense irradiation of the reaction. These irradiation
conditions were tested, and when quinone 35 was irradiated
with a sunlamp in the presence of ethanethiol, only the pyr-
1
role 51 was observed by H NMR spectroscopy. The in-
ternal redox reaction to 35a had been successful, but pre-
sumably further oxidation by oxygen in the system had oc-
curred instead of the desired alkylation.
It is known that the presence of electronegative substitu-
ents on the pyrrole nitrogen atom suppresses the azafulvene
mechanism of substitution, which explains why the pyrrolo-
quinones 51 and 52 do not react with ethanethiol.[15] Be-
cause the reaction had proceeded rapidly (15 min) and
yielded no evidence of the hydroquinone, it was postulated
that premature air oxidation of the desired hydroquinone
to the quinone oxidation state was preventing alkylation.
Experiments with ambient light were carried out with the
hope that a less intense light source at lower temperature
might lengthen the lifetime of the hydroquinone. Unfortu-
Scheme 5. Synthesis of 2,4-disubstituted-3-pyrrolines 28 and 13.
The 3-pyrrolines 14 and 15 were obtained from 29 and nately, while the quinone 34 underwent the internal redox
30 in a straightforward manner by reduction and acylation reaction, the resultant hydroquinone was again oxidized to
(Scheme 6). The known diesters 29 and 30 were prepared the quinone 52 before alkylation could occur. Additionally,
from the corresponding pyrroles by taking advantage of irradiation of degassed solutions of 34 yielded only intrac-
Donohoe’s flexible partial reduction method.[13]
table mixtures.
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2-(3-Pyrrolin-1-yl)-1,4-naphthoquinones: Photoactivated Alkylating Agents
Table 1. Michael addition of 3-pyrrolines.
[a] Conditions: (1) TFA, CH2Cl2. (2) NH4OH, MeOH; naphthoquinone, CuBr, Et2O. [b] Conditions: (1) TFA, CH2Cl2. (2) Et3N, THF;
quinolinequinone, CeCl3·7H2O, EtOH. [c] The compound was found to be unstable to storage for prolonged periods. [d] Variable results
were observed giving 0–12% yield, but in any case the reaction was not preparatively useful. [e] Decomposition.
Fortunately, a combination of a better leaving group and leaving group, the (chloromethyl)-3-pyrroline 36 gave the
less intense irradiation provided an encouraging result. desired sulfide 53 in 54% yield. In both cases, we did not
When the acetate 35 was treated with ethanethiol in the observe the presumed hydroquinone species.
presence of ambient room light, a small amount of the de-
In order to determine whether the proposed hydro-
sired alkylated product was isolated along with 53% of the quinone–pyrroline intermediate was responsible for the suc-
non-alkylated product 51 (Scheme 8). Moving to a better cessful alkylation, we carried out several experiments. Con-
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A. Aponick, A. L. Dietz, W. H. Pearson
Table 2. Optimization studies.
FULL PAPER
Entry[a]
Solvent
Base
hν
Time
Yield
1
2
3
4
5
6
7
toluene
CH2Cl2
toluene
CH3CN
CHCl3
CHCl3
CHCl3
–
–
–
–
–
sunlamp
sunlamp
ambient
ambient
ambient
ambient
1 h
1 h
3 d
1 d
1 d
2 d
2 d
22%
26%
40%
34%
54%
51%
63%
K2CO3
2,6-luti- ambient
dine
8
9
MeOH
MeOH
–
ambient
3 d
1 d
0%
0%
2,6-luti- ambient
dine
Scheme 7. Initial irradiation studies.
[a] 10 mol-equiv. of EtSH employed.
Scheme 8. Initial alkylation studies.
trol experiments excluding light from the reaction under
conditions otherwise identical led to only the observation
of the starting materials 35 and 36, demonstrating that no
chemistry can occur prior to light activation. To probe the
issue of whether the alkylation occurs before or after oxi-
dation of the hydroquinone to the quinone, the 3-pyrroline
36 was oxidized to the pyrrole 54 and exposed to the alky-
lation reaction conditions (Scheme 9). The pyrrole 54 failed
to undergo a significant amount of alkylation (Ͻ10%) indi-
cating that while 54 may participate in the reaction to some
extent that it is likely a minor pathway and that the corre-
sponding hydroquinone is the most likely reactive species.
Scheme 9. Control experiment to determine when alkylation oc-
curs.
Scheme 10. Light-triggered alkylation reactions of mono(electro-
philes).
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2-(3-Pyrrolin-1-yl)-1,4-naphthoquinones: Photoactivated Alkylating Agents
The reaction was next optimized for light source, solvent, the hydroquinones 59 and 60 were isolated and charac-
time, and additive (Table 2). It was found that the best yield terized. These compounds were found to slowly undergo
was obtained by using ambient light in chloroform with 2,6- oxidation to the corresponding quinones, but were charac-
lutidine as an additive to remove HCl generated during the terized in the hydroquinone oxidation state. It was gratify-
reaction. To provide the best mimic for biological systems, ing that these two reactions proceeded in nearly 80% for
it was hoped that the reaction would function in a polar each, demonstrating that the designed sequence could be
protic solvent, but unfortunately the use of methanol pro- very efficient.
vided no product.
With these conditions established, alkylation studies with
Conclusions
the remaining monoalkylators are outlined in Scheme 10.
Alkylation of the naphthoquinone 38 with the electrophilic
group in the 2-position proceeded in 86% yield without any
added base. Likewise, alkylation of the quinolinequinones
47 and 48 showed the same trend. The 2-substituted 3-
pyrroline reacted substantially better, although it is interest-
ing that the hydroquinone oxidation states of these com-
pounds are stable enough to be isolated without further oxi-
dation to the corresponding quinones, further validating
our hypothesis that hydroquinones are involved in the alky-
lation. The juglone 42 also functioned in the reaction, but
the isoquinolinequinones 44 and 45 failed to undergo even
the initial internal redox reaction.
A diverse array of 2-(3-pyrrolin-1-yl)-1,4-naphthoqui-
nones were prepared by Michael addition of the corre-
sponding 3-pyrrolines with the requisite quinones. The reac-
tion was found to be quite general and effective when car-
ried out in the absence of light. The target compounds were
observed to undergo an internal redox reaction triggered by
ambient room light to generate reactive pyrroles that are
then alkylated by ethanethiol. This provides a proof of prin-
ciple for the potential use of these compounds as photoacti-
vated alkylating agents.
Alkylation of the bis(electrophiles) 39, 40, 48, and 49
were studied with hopes that the sequence involving redox,
two ionization/alkylation steps, and oxidation to the qui-
none would be as efficient as the alkylation reactions de-
scribed in Scheme 10. As outlined in Scheme 11, the chem-
istry worked as planned, but the products of the reactions
employing naphthoquinones 39 and 40 were unusual in that
Experimental Section
General: Unless otherwise noted, reactions were carried out under
dry nitrogen in flame-dried glassware equipped with tightly fitted
rubber septum. Toluene, triethylamine, pyridine, dichloromethane,
diethylamine, and diisopropylamine were distilled from powdered
calcium hydride. Dimethylformamide (DMF) was distilled at re-
duced pressure from barium oxide. Tetrahydrofuran (THF) and di-
ethyl ether were distilled under nitrogen from sodium/benzophe-
none ketyl. Commercial n-butyllithium was titrated with di-
phenylacetic acid prior to use. Reagents which required preparation
according to literature procedures are referenced when described.
All other reagents were obtained from Aldrich Chemical Company,
and used without further purification. Chromatography refers to
liquid chromatography on silica gel. Proton nuclear magnetic reso-
nance (1H NMR) spectra were recorded at 500, 400 or 300 MHz
respectively, with Varian Unity INOVA 500, Varian Unity INOVA
400 or Varian Mercury 300 spectrometers. Chemical shifts (δ) are
reported in parts per million (ppm) downfield relative to tetrameth-
ylsilane (TMS). Coupling constants (J) are reported in Hz. Multi-
plicities are reported by using the following abbreviations: s, singlet;
d, doublet; t, triplet; q, quartet; m, multiplet; br., broad. 13C NMR
spectra were recorded with a Varian Unity INOVA 400 spectrome-
ter at 100 MHz, and chemical shifts are reported in ppm relative
to the carbon resonance of CDCl3 (δ = 77.06 ppm). Infrared (IR)
spectra were obtained with a Perkin Elmer Spectrum BX FT-IR
spectrometer at 2.0 cm–1 resolution and are reported in wave-
numbers (signal intensity and shape). The following abbreviations
are used in describing IR data: w, weak; m, medium; s, strong; br.,
broad. UV/Vis spectra were recorded with a Shimadzu UV160U
spectrophotometer. Routine mass spectrometric data were obtained
by using a Hewlett Packard 6890 gas chromatograph equipped with
an HP 5973 mass-selective detector (GCMS) by electron impact
(EI) at 70 eV. High resolution mass spectral (HRMS) and elemental
analyses were performed by the facilities operated by the University
of Michigan.
tert-Butyl Allyl[2-(chloromethyl)allyl]carbamate (18): N-Boc-Allyl-
amine (16) (0.157 g, 1.00 mmol) and 3-chloro-2-(chloromethyl)-1-
propene (0.125 g, 1.00 mmol) were dissolved in DMF (2.5 mL).
Scheme 11. Light-triggered alkylation reactions of bis(electro-
philes).
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A. Aponick, A. L. Dietz, W. H. Pearson
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NaH (0.06 g of a 60% dispersion in light mineral oil, 1.5 mmol)
was added to the clear colorless solution which immediately turned
to a cloudy pale yellow. After 1 h, the reaction was quenched by
dropwise addition of H2O (25 mL), then diluted with diethyl ether
(ca. 25 mL). The layers were separated, and the organic layer was
washed successively with three portions of H2O, then brine, dried
(MgSO4), and the solvent removed in vacuo. Chromatography (0–
6% EtOAc/hexane gradient) afforded 0.15 g (61%) of a colorless
oil. Rf = 0.29 (10% EtOAc/hexanes). 1H NMR (400 MHz, CDCl3):
mmol) was dissolved in CH2Cl2 (5 mL). Grubb’s catalyst (0.0102 g,
0.0124 mmol, 5 mol-%) was added and the mixture refluxed for 7 h.
The reaction mixture was then cooled to room temp., opened to
air, and stirred for 15 h. The crude reaction mixture was then ad-
sorbed onto silica gel and immediately chromatographed (25–50%
EtOAc/hexanes gradient) to give 0.0435 g (88%) of a brown oil. Rf
= 0.30 (50% EtOAc/hexanes). 1H NMR (400 MHz, CDCl3,
–20 °C): δ = 5.56 (d, J = 9.2 Hz, 1 H), 4.29 (br. s, 1 H), 4.09 (s, 2
H), 4.02–4.00 (m, 4 H), 1.37 (s, 9 H) ppm. 13C NMR (100 MHz,
δ = 5.82–5.72 (m, 1 H), 5.27 (s, 1 H), 5.16–5.05 (m, 3 H), 4.03 (s, CDCl3, –20 °C): δ = 154.4, 154.4, 139.5, 139.3, 119.6, 119.5, 79.6,
2 H), 3.93 (s, 2 H), 3.82–3.78 (m, 2 H) 1.46 (s, 9 H) ppm. 13C NMR 79.6, 59.2, 59.2, 53.1, 53.0, 52.7, 52.6, 28.2, 28.2 ppm. IR (neat): ν
˜
(100 MHz, CDCl3): δ = 155.5, 141.3, 133.6, 116.9, 116.0, 80.0, 48.9,
48.3, 45.7, 28.4. IR (neat): ν = 3083 (w), 2978 (m), 2930 (m), 1697
= 3429 (m, br.), 2970 (m), 2860 (m), 1702 (s), 1682 (s), 1657 (s),
1412 (s) cm–1. LRMS (EI, 70 eV): m/z (%) = 199 (0.094), 184
˜
(s), 1645 (m), 1457 (s), 1404 (s), 1366 (s) cm–1. LRMS (EI, 70 eV): (0.021), 142 (25), 126 (22), 112 (19), 98 (6), 80 (15), 68 (54), 57
m/z (%) = 245 (0.036), 210 (2), 189 (17), 172 (19), 154 (100), 110
(32), 57 (78). HRMS (CI with NH3): calcd. for C12H21ClNO2 [M
+ H]+ 246.1261; found 246.1249. C12H20ClNO2 (245.12): calcd. C
58.65, H 8.20, N 5.70; found C 58.63, H 8.20, N 5.47.
(100). HRMS (CI, NH3): calcd. for C10H18NO3 [M + H]+
200.1287; found 200.1288. C10H17NO3 (200.13): calcd. C 60.28, H
8.60, N 7.03; found C 60.41, H 8.60, N 6.97.
tert-Butyl 3-(Chloromethyl)-2,5-dihydropyrrole-1-carbamate (10): (Ben-
zylidene)dichloridobis(tricyclohexylphosphane)ruthenium (0.286 g,
0.35 mmol) was added to 18 (1.71 g, 6.96 mmol) in CH2Cl2
(130 mL), and the mixture was heated to reflux. After 16 h, the
reaction was not progressing so an additional portion of the cata-
lyst (60 mg, 73 µmol) was added. The reaction’s progression had
stopped again after 24 h, and another portion of the catalyst
(60 mg, 73 µmol) was added. After a total of 3 d, the mixture was
cooled to room temp., opened to air for 24 h, and then concen-
trated. The residue was chromatographed (5% to 20% ethyl ace-
tate/hexanes, gradient) to yield 1.34 g (88%) of the title compound.
tert-Butyl [2-(Acetoxymethyl)allyl]allylcarbamate (19): Compound
18 (0.154 g, 0.630 mmol) was dissolved in DMF (1.6 mL), and to
the solution was added KOAc (0.068 g, 0.69 mmol). The reaction
mixture was heated to 65 °C for 3.5 h, cooled to room temp., then
diluted with water (10 mL) and diethyl ether (10 mL). The layers
were separated, and the organic layer was washed successively with
three portions of H2O, then brine, dried (MgSO4), and the solvent
removed in vacuo to yield 0.155 g (91%) of a clear colorless oil
which was typically used without further purification. An analyti-
cally pure sample was obtained by chromatography (5% EtOAc/
hexanes). Rf = 0.16 (10% EtOAc/hexanes). 1H NMR (400 MHz,
CDCl3): δ = 5.84–5.68 (m, 1 H), 5.18–5.04 (m, 4 H), 4.53 (s, 2 H),
3.90–3.75 (m, 4 H), 2.09 (s, 3 H), 1.45 (s, 9 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 170.5, 155.5, 140.0, 133.7, 116.5, 114.6,
R = 0.13 (10% ethyl acetate/hexanes). IR (neat): ν = 1700 (s) cm–1.
˜
f
1H NMR (400 MHz, CDCl3, containing rotamers): δ = 5.70 (d, J
= 17.5 Hz, 1 H), 4.11–4.00 (m, 1 H), 4.06 (s, 2 H), 4.04 (s, 2 H),
1.38 (s, 9 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 153.96,
135.48, 135.41, 124.41, 124.38, 79.31, 79.26, 52.96, 52.80, 40.14,
40.08, 28.17 ppm. MS (EI, 70 eV): m/z (%) = 57 (100) [tBu]+.
HRMS (CI/NH3): calcd. for C10H16ClNO2 [M + H]+ 218.0948;
found 218.0943.
78.9, 65.0, 48.6, 48.3, 28.3, 20.8 ppm. IR (neat): ν = 3083 (w), 2977
˜
(m), 2931 (m), 1745 (s), 1697 (s), 1456 (s), 1405 (s), 1366 (s) cm–1.
LRMS (CI with NH3): m/z (%) = 270 (16), 231 (65), 214 (29), 170
(100). HRMS (CI with NH3): calcd. for C14H24NO4 [M +
H]+ 270.1714; found 270.1705. C14H23NO4 (269.16): calcd. C 62.43,
H 8.61, N 5.20; found C 62.63, H 8.39, N 5.15.
tert-Butyl 2-(Acetoxymethyl)-2,5-dihydropyrrole-1-carbamate (12):
Acetic anhydride (0.161 mL, 1.71 mmol) was added to tert-butyl 2-
(hydroxymethyl)-2,5-dihydropyrrole-1-carboxylate (11) (0.113 g,
0.57 mmol) in CH2Cl2 (12 mL), followed by the addition of 4-(di-
methylamino)pyridine (0.209 g, 1.71 mmol). After 16 h, the mixture
was diluted with ethyl acetate, washed (saturated NaHCO3, then
brine), dried (Na2SO4), and concentrated. The residue was chro-
matographed (10% ethyl acetate/hexanes) to yield 0.133 g (96%) of
the title compound. Rf = 0.12 (10% ethyl acetate/hexanes). IR
tert-Butyl Allyl[2-(hydroxymethyl)allyl]carbamate: tert-Butyl [2-
(acetoxymethyl)allyl]allylcarbamate (19) (0.155 g, 0.57 mmol) and
methanol (2.9 mL) were mixed to form a cloudy solution. Potas-
sium carbonate (0.079 g, 0.57 mmol) was dissolved in a minimal
amount of H2O (0.25 mL) and added to the solution. The reaction
mixture was stirred for 2.5 h then diluted with H2O (ca. 10 mL),
and the methanol removed in vacuo. The mixture was extracted
with three portions of CH2Cl2, and the combined organic extracts
werer dried (MgSO4). The solvent was removed in vacuo to yield
0.118 g (91%) of a clear colorless oil which was typically used with-
out further purification. An analytically pure sample was obtained
by chromatography (10–25% EtOAc/hexanes gradient). Rf = 0.30
(25% EtOAc/hexanes). 1H NMR (300 MHz, CDCl3): δ = 5.71–5.80
(m, 1 H), 5.17–5.08 (m, 3 H), 4.93 (s, 1 H), 4.01 (s, 2 H), 3.89 (s, 2
H), 3.74 (s, 2 H), 3.34 (br. s, 1 H), 1.46 (s, 9 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 156.6, 144.9, 133.4, 116.8, 113.6, 80.4, 63.7,
(neat): ν = 1745 (s), 1698 (s) cm–1. 1H NMR (400 MHz, CDCl3,
˜
containing rotamers): δ = 5.80 (s, 0.56 H), 5.73 (s, 0.43 H), 5.62 (s,
1 H), 4.64 (s, 0.43 H), 4.53 (s, 0.56 H), 4.29 (dd, J = 20.7, 10.6 Hz,
1 H), 4.16–3.94 (m, 3 H), 1.94 (s, 3 H), 1.40 (s, 9 H) ppm. 13C
NMR (100 MHz, CDCl3): δ = 170.68, 154.00, 153.86, 127.13,
126.93, 79.84, 79.47, 64.34, 63.86, 63.04, 62.82, 53.57, 53.42, 28.21,
20.57, 20.56 ppm. MS (EI, 70 eV): m/z (%) = 168 (44) [M –
OtBu]+, 126 (44) [M – C2H2O – OtBu]+, 112 (100) [M + H – tBu –
CH2O2CCH3]+. HRMS (ESI): calcd. for C12H19NO4 [M + Na]+
264.1212; found 264.1217.
49.0, 48.4, 28.3 ppm. IR (neat): ν = 3442 (m, br), 3082 (w), 2977
˜
(w), 2929 (m), 1696 (s), 1675 (s), 1458 (s), 1410 (s), 1366 (s) cm–1.
LRMS (EI, 70 eV): m/z (%) = 227 (0.086), 171, (29), 154 (13), 126
(10), 100 (28), 57 (100). HRMS (CI, with NH3): calcd. for
C12H22NO3 [M + H]+ 228.1600; found 228.1597. C12H21NO3
(227.15): calcd. C 63.41, H 9.31, N 6.16; found C 63.49, H 9.34, N
6.07.
tert-Butyl 1-[(Triisopropylsilyloxy)methyl]allylcarbamate (25): Imid-
azole (19.8 mg, 0.29 mmol) was added to tert-butyl 1-(hy-
droxymethyl)allylcarbamate (24) (18.1 mg, 97.0 µmol) and triiso-
propylsilyl chloride (30 µL, 0.14 mmol) in DMF (0.25 mL). After
2 h, the mixture was diluted with CH2Cl2, washed with water, dried
tert-Butyl 3-(Hydroxymethyl)-2,5-dihydropyrrole-1-carbamate (11): (Na2SO4), and concentrated. The residue was chromatographed
tert-Butyl allyl[2-(hydroxymethyl)allyl]carbamate (0.0564 g, 0.248 (1% to 5% ethyl acetate/hexanes, gradient) to yield 33.3 mg (100%)
4270
www.eurjoc.org
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 4264–4276

2-(3-Pyrrolin-1-yl)-1,4-naphthoquinones: Photoactivated Alkylating Agents
of the title compound. Rf = 0.32 (5% ethyl acetate/hexanes). IR
15.0 Hz, 1 H), 4.10 (s, 2 H), 3.74 (dd, J = 11.4, 5.1 Hz, 1 H), 3.58
(neat): ν = 3354 (br.), 1720 (s) cm–1. 1H NMR (400 MHz, CDCl ): (dd, J = 11.4, 7.3 Hz, 1 H), 1.48 (s, 9 H) ppm. 13C NMR (100 MHz,
˜
3
δ = 5.83 (ddd, J = 17.2, 10.4, 5.4 Hz, 1 H), 5.18 (d, J = 17.2 Hz, 1
H), 5.10 (dt, J = 10.2, 1.5 Hz, 1 H), 4.84 (s, 1 H), 4.14 (s, 1 H),
3.74 (dd, J = 9.5, 4.4 Hz, 1 H), 3.68 (dd, J = 9.7, 4.4 Hz, 1 H), 1.41
(s, 9 H), 1.04 (s, 3 H), 1.02 (s, 18 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 155.50, 136.72, 115.46, 79.16, 65.64, 54.36, 28.26,
17.80, 11.77 ppm. MS (EI, 70 eV): m/z (%) = 270 (8) [M –
OtBu]+, 244 (100) [M – OtBu – C2H2]+. HRMS (ESI): calcd. for
C18H37NO3Si [M + Na]+ 366.2440; found 366.2430.
CDCl3) δ = 156.25, 136.49, 125.23, 80.79, 67.77, 66.51, 54.13,
39.86, 28.25 ppm. MS (EI, 70 eV): m/z (%) = 57 (100) [tBu]+.
HRMS (ESI): calcd. for C11H18ClNO3 [M + H]+ 248.1053; found
248.1055.
tert-Butyl 2-(Acetoxymethyl)-4-(chloromethyl)-2,5-dihydropyrrole-1-
carbamate (13): Acetic anhydride (0.164 mL, 1.74 mmol) was added
to 28 (0.145 g, 0.580 mmol) in CH2Cl2 (12 mL), followed by the
addition of 4-(dimethylamino)pyridine (0.212 g, 1.74 mmol). After
1.5 h, the mixture was diluted with ethyl acetate, washed (saturated
NaHCO3, then brine), dried (Na2SO4), and concentrated. The resi-
due was chromatographed (10% to 20% ethyl acetate/hexanes, gra-
dient) to yield 0.143 g (85%) of the title compound. Rf = 0.32 (10%
tert-Butyl [2-(Chloromethyl)allyl]{1-[(triisopropylsilyloxy)methyl]-
allyl}carbamate (26): Sodium hydride (0.296 g of 60 wt.-% suspen-
sion in mineral oil, 7.4 mmol) was added to 25 (1.27 g, 3.7 mmol)
and 3-chloro-2-(chloromethyl)-1-propene (0.856 mL, 7.4 mmol) in
DMF (9 mL). After 4 h, water (3 mL), was slowly added, and the
mixture was extracted with diethyl ether, washed with water, dried
(MgSO4) and concentrated. The residue was chromatographed (1%
to 5% ethyl acetate/hexanes, gradient) to yield 1.04 g (65%) of the
ethyl acetate/hexanes). IR (neat): ν = 1743 (s), 1701 (s) cm–1. 1H
˜
NMR (400 MHz, CDCl3, containing rotamers): δ = 5.71 (d, J =
5.9 Hz, 1 H), 4.74 (s, 0.5 H), 4.62 (s, 0.5 H), 4.40 (ddd, J = 23.2,
10.8, 2.9 Hz, 1 H), 4.28 (d, J = 15.0 Hz, 1 H), 4.21–4.07 (m, 4 H),
2.02 (s, 3 H), 1.48 (s, 9 H) ppm. 13C NMR (100 MHz, CDCl3): δ
title compound. R = 0.36 (5% ethyl acetate/hexanes). IR (neat): ν
˜
f
1
= 1699 (s) cm–1. H NMR (400 MHz, CDCl3): δ = 5.90 (s, 1 H), = 170.74, 153.87, 137.17, 136.93, 125.80, 125.59, 80.23, 79.91,
5.19–5.07 (m, 4 H), 4.34–4.15 (m, 1 H), 4.07–3.83 (m, 1 H), 4.05
(d, J = 13.2 Hz, 1 H), 4.00 (s, 2 H), 3.85 (d, J = 16.8 Hz, 1 H),
3.76 (dd, J = 10.1, 5.5 Hz, 1 H), 1.40 (s, 9 H), 1.02 (s, 18 H), 1.01
78.16, 63.57, 53.69, 53.55, 39.91, 39.80, 28.26, 20.60 ppm. MS (EI,
70 eV): m/z (%) = 160 (72) [M + H – tBu – CH2OAc]+, 57 (100)
[tBu]+. HRMS (ESI): calcd. for C13H20ClNO4 [M + Na]+ 312.0979;
(s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 155.18, 141.82, found 312.0987.
134.69, 117.33, 115.33, 79.75, 70.28, 64.04, 61.40, 48.73, 45.93,
tert-Butyl (2R*,5S*)-2,5-Bis(acetoxymethyl)-2,5-dihydropyrrole-1-
28.20, 17.82, 11.74 ppm. MS (EI, 70 eV): m/z (%) = 332 (100) [M
+ H – tBu – iPr]+, 188 (58) [M + H – CH2OTips – tBu]+, 144 (72)
[M – CH2OTIPS – OtBu – C2H3]+, 57 (91) [tBu]+. HRMS (ESI):
calcd. for C22H42ClNO3Si [M + Na]+ 454.2520; found 454.2530.
carbamate (14): The ester 29[13] (0.147 g, 0.515 mmol) in THF
(1.25 mL) was added slowly to LiBH4 (33.7 mg, 1.54 mmol) in
THF (3.75 mL). After 1 h, 1  HCl (4 mL) was added dropwise,
and the mixture was extracted with ethyl acetate, dried (MgSO4),
tert-Butyl [2-(Chloromethyl)allyl][1-(hydroxymethyl)allyl]carbamate and concentrated. The residue was dissolved in CH2Cl2 (10 mL),
(27): Tetrabutylammonium fluoride (4.4 mL of a 1.0  solution in and acetic anhydride (0.243 mL, 2.57 mmol) and 4-(dimeth-
THF, 4.4 mmol) was added slowly to 26 (0.968 g, 2.20 mmol) in ylamino)pyridine (0.189 g, 1.54 mmol) were added in succession.
THF (44 mL). After 15 min, ethyl acetate was added, and the mix-
ture was washed with brine. The aqueous layer was extracted with
ethyl acetate, and the combined organic layers were dried (Na2SO4)
and concentrated. The residue was chromatographed (5% to 30%
ethyl acetate/hexanes, gradient) to yield 0.523 g (86%) of the title
After 2 h, the mixture was diluted with ethyl acetate, washed (satu-
rated NaHCO3, then brine), dried (Na2SO4), and concentrated.
The residue was chromatographed (20% ethyl acetate/hexanes) to
yield 0.131 g (81%) of the title compound. Rf = 0.22 (20% ethyl
1
acetate/hexanes). IR (neat): ν = 1743 (s), 1700 (s) cm–1. H NMR
˜
compound. R = 0.32 (30% ethyl acetate/hexanes). IR (neat): ν =
(400 MHz, CDCl3): δ = 5.75 (d, J = 6.6 Hz, 1 H), 5.70 (d, J =
˜
f
3450 (br), 1693 (s) cm–1. 1H NMR (400 MHz, CDCl3): δ = 5.89 6.2 Hz, 1 H), 4.67 (q, J = 2.2 Hz, 1 H), 4.55 (dd, J = 5.1, 4.8 Hz,
(ddd, J = 17.0, 10.2, 6.6 Hz, 1 H), 5.26 (s, 2 H), 5.23 (d, J =
10.6 Hz, 1 H), 5.16 (d, J = 17.2 Hz, 1 H), 5.12 (s, 1 H), 4.23 (q, J 1 H), 4.34 (dd, J = 11.0, 5.1 Hz, 1 H), 4.20 (dd, J = 11.0, 5.1 Hz,
= 6.2 Hz, 1 H), 4.10–3.76 (m, 4 H), 4.04 (s, 2 H), 2.05 (s, 1 H), 1.45
1 H), 2.05 (s, 3 H), 1.48 (s, 9 H) ppm. 13C NMR (100 MHz,
(s, 9 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 156.16, 142.08, CDCl3): δ = 170.89, 154.17, 128.65, 80.57, 65.20, 64.72, 63.75,
1 H), 4.47 (dd, J = 10.8, 5.1 Hz, 1 H), 4.38 (dd, J = 11.0, 2.2 Hz,
133.69, 117.86, 115.83, 80.59, 63.40, 61.68, 51.28, 48.25, 45.74,
63.53, 28.32, 20.79 ppm. MS (EI, 70 eV): m/z (%) = 124 (94) [M –
28.11 ppm. MS (EI, 70 eV): m/z (%) = 188 (52) [M + H – tBu –
tBu – CH2OAc – OAc]+, 80 (100) [M – Boc – CH2OAc – OAc]+,
CH2OH]+, 144 (64) [M – CH2OH – C2H3 – OtBu]+, 57 (100) [tBu]+. 57 (52) [tBu]+. HRMS (ESI): calcd. for C15H23NO6 [M + Na]+
HRMS (ESI): calcd. for C13H22ClNO3 [M + Na]+ 298.1186; found
298.1190.
336.1423; found 336.1419.
tert-Butyl (2S*,5S*)-2,5-Bis(acetoxymethyl)-2,5-dihydropyrrole-1-
tert-Butyl 4-(Chloromethyl)-2-(hydroxymethyl)-2,5-dihydropyrrole- carbamate (15): 1-tert-Butyl 2,5-dimethyl trans-2,5-dihydropyrrole-
1-carbamate Acid (28): [1,3-Bis(2,4,6-trimethylphenyl)-2-imidazol-
idinylidene]dichlorido(phenylmethylene)(tricyclohexylphosphane)-
ruthenium (Grubbs’ catalyst, 2nd generation) (0.144 g, 0.17 mmol)
1,2,5-tricarboxylate (30) (106 mg, 0.371 mmol) in THF (0.5 mL)
was added slowly to super hydride (1.86 mL of a 1.0  solution in
THF, 1.86 mmol) in THF (1.5 mL). After 20 h, 1  HCl (1.5 mL)
was added to 27 (0.937 g, 3.40 mmol) in CH2Cl2 (68 mL), and the was added dropwise, and the mixture was extracted with ethyl ace-
mixture was heated to reflux. After 10 h, the reaction was not pro-
gressing so an additional portion of the catalyst (62 mg, 73 µmol)
was added. After a total of 15 h, the mixture was cooled to room
temp. and then concentrated. The residue was chromatographed
(20% to 30% ethyl acetate/hexanes, gradient) to yield 0.830 g
(98%) of the title compound. Rf = 0.42 (40% ethyl acetate/hex-
tate, dried (MgSO4), and concentrated. The residue was dissolved
in CH2Cl2 (7.5 mL), and acetic anhydride (0.175 mL, 1.85 mmol)
and 4-(dimethylamino)pyridine (136 mg, 1.11 mmol) were added in
succession. After 1 h, the mixture was diluted with ethyl acetate,
washed (saturated NaHCO3, then brine), dried (Na2SO4), and con-
centrated. The residue was chromatographed (20% ethyl acetate/
hexanes) to yield 95.0 mg (82%) of the title compound. Rf = 0.20
anes). IR (neat): ν = 3409 (br.), 1698 (s) cm–1. 1H NMR (400 MHz,
˜
CDCl3, containing rotamers): δ = 5.63 (s, 1 H), 4.74 (s, 1 H), 4.50
(d, J = 7.4 Hz, 1 H), 4.23 (d, J = 15.0 Hz, 1 H), 4.12 (d, J =
(20% ethyl acetate/hexanes). IR (neat): ν = 1743 (s), 1698 (s) cm–1.
˜
1H NMR (400 MHz, CDCl3): δ = 5.75 (d, J = 6.6 Hz, 1 H), 5.70
Eur. J. Org. Chem. 2008, 4264–4276
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4271

A. Aponick, A. L. Dietz, W. H. Pearson
FULL PAPER
(d, J = 6.2 Hz, 1 H), 4.67 (q, J = 2.2 Hz, 1 H), 4.55 (dd, J = 6.8,
5.1 Hz, 1 H), 4.47 (dd, J = 10.8, 2.6 Hz, 1 H), 4.39 (dd, J = 11.0,
2.2 Hz, 1 H), 4.34 (dd, J = 11.0, 5.1 Hz, 1 H), 4.20 (dd, J = 11.0,
5.1 Hz, 1 H), 1.99 (s, 3 H), 1.45 (s, 9 H) ppm. 13C NMR (100 MHz,
and the organic layer was washed with NaOH solution (20 mL),
followed by H2O (2ϫ 20 mL). The extract was dried (MgSO4) and
the solvent removed in vacuo. Chromatography (0–30% EtOAc/
hexanes gradient) afforded 0.0817 g (quantitative yield) of a red
CDCl3): δ = 170.68, 153.21, 128.56, 128.42, 80.46, 65.19, 63.71, solid. Rf = 0.045 (20% EtOAc/hexanes). M.p. 119.5–121 °C. 1H
63.57, 62.65, 28.29, 20.61 ppm. MS (EI, 70 eV): m/z (%) = 124 (95) NMR (400 MHz, CDCl3): δ = 8.07 (dd, J = 7.8, 1.2 Hz, 1 H), 8.04
[M – tBu – CH2OAc – OAc]+, 80 (100) [M – Boc – CH2OAc –
OAc]+, 57 (56) [tBu]+. HRMS (ESI): calcd. for C15H23NO6 [M +
Na]+ 336.1423; found 336.1423.
(dd, J = 7.8, 1.2 Hz, 1 H), 7.71 (dt, J = 7.8, 1.2 Hz, 1 H), 7.62 (dt,
J = 7.8, 1.2 Hz, 1 H), 5.91 (s, 1 H), 5.73 (s, 1 H), 5.17–4.58 (m, 4
H), 4.19 (br. s, 2 H), 2.11 (s, 3 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 182.7, 182.5, 170.5, 147.6, 136.2, 134.1, 133.0, 131.9,
131.6, 126.4, 125.5, 120.7, 105.3, 60.5, 57.8 (br., 2 C), 20.7 ppm. IR
2-[3-(Hydroxymethyl)-2,5-dihydropyrrol-1-yl]-1,4-naphthoquinone
(34): tert-Butyl 3-(hydroxymethyl)-2,5-dihydropyrrole-1-carboxyl-
ate (8) (0.1197 g, 0.6013 mmol) was dissolved in CH2Cl2 (1.4 mL),
and trifloroacetic acid (0.46 mL, 6.013 mmol) was added dropwise.
The reaction mixture was stirred for 1 h, at which time the solvent
and excess trifluoroacetic acid were removed in vacuo to leave the
trifloroacetic acid salt of the free amine which was used without
purification. The crude amine salt was neutralized by the addition
of a 0.2  solution of NH4OH in methanol (3.1 mL, 0.62 mmol).
A second solution containing naphthoquinone (0.0951 g,
(neat): ν = 3067 (w), 2919 (w), 2848 (w), 1738 (s), 1673 (s), 1622
˜
(s), 1593 (s), 1565 (s), 1267 (s) cm–1. UV (CHCl3): λmax = 246, 276,
464, 642 nm (logε = 4.04, 4.15, 3.56, 2.81). LRMS (CI, NH3): m/z
(%) = 298 (24), 240 (100), 224 (21), 82 (19). HRMS (CI, NH3):
calcd. for C17H16NO4 [M + H]+ 298.1079; found 298.1073.
C
17H15NO4 (297.10): calcd. C 68.66, H 5.09, N 4.71; found C
68.67, H 5.07, N 4.47.
2-[3-(Chloromethyl)-2,5-dihydropyrrol-1-yl]-1,4-naphthoquinone
0.6013 mmol) and copper(I) bromide (0.0086 g, 0.06013 mmol) in (36): Trifluoroacetic acid (0.619 mL, 8.0 mmol) was added to 10
diethyl ether (3 mL) was prepared, and the flask wrapped in alumi-
num foil to protect it from ambient light. In a dark fume hood, the
amine solution was added dropwise to the solution of the quinone.
Upon addition of the first few drops, the solution turned from a
deep gold color to red. The reaction mixture, open to air, was
stirred for 15 h, then the solvent removed in vacuo. The residue
was taken up in water and CH2Cl2, the layers were separated, the
organic layer was extracted with 3 portions of CH2Cl2. The com-
bined organic extracts were dried (MgSO4), and the solvent was
removed in vacuo to yield an orange solid. Chromatography (50–
100% EtOAc/hexanes gradient) afforded 0.0930 g of an orange
crystalline solid. Rf = 0.23 (EtOAc). M.p. 163–164 °C. 1H NMR
(400 MHz, CDCl3, 3 drops of CD3OD): δ = 8.04 (dd, J = 7.6,
1.2 Hz, 1 H), 8.01 (dd, J = 7.6, 1.2 Hz, 1 H), 7.71 (dd, J = 7.6,
1.2 Hz, 1 H), 7.62 (dd, J = 7.6, 1.2 Hz, 1 H), 5.83 (s, 1 H), 5.69 (s,
1 H), 4.78 (s, 2 H), 4.28 (s, 2 H), 4.21 (br. s, 2 H) ppm. 13C NMR
(175 mg, 0.800 mmol) in CH2Cl2 (8 mL). After 2 h, the mixture was
concentrated and exposed to high vacuum for 1 h. The residue was
dissolved in THF (8 mL), and triethylamine (123 µL, 0.88 mmol)
was added. After 10 min, this mixture was added to 1,4-naphtho-
quinone (126 mg, 0.800 mmol) and copper(I) bromide (23.0 mg,
0.160 mmol) in THF (4 mL) in the dark. The mixture was heated
to reflux open to air in the dark. After 16 h, it was cooled to room
temp. and concentrated. The residue was chromatographed (20%
to 40% ethyl acetate/hexanes, gradient) to yield 111 mg (51%) of
the title compound. Rf = 0.11 (25% ethyl acetate/hexanes). IR
(neat): ν = 1668 (s), 1617 (s), 1591 (m), 1557 (s) cm–1. 1H NMR
˜
(500 MHz, CDCl3): δ = 8.05 (dd, J = 7.6, 0.7 Hz, 1 H), 8.02 (dd,
J = 7.7, 0.7 Hz, 1 H), 7.70 (td, J = 7.6, 1.5 Hz, 1 H), 7.61 (td, J =
7.7, 1.5 Hz, 1 H), 5.96 (s, 1 H), 5.69 (s, 1 H), 4.81 (s, 2 H), 4.22 (s, 4
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 182.81, 182.63, 147.86,
134.27, 132.99, 132.01, 131.58, 126.49, 125.58, 105.33, 58.11,
(100 MHz, CDCl3): δ = 183.0, 182.7, 148.0, 134.2, 133.1, 131.9, 39.85 ppm. MS (EI, 70 eV): m/z (%) = 273 (38) [M]+, 238 (100)
131.7, 126.5, 125.6, 105.1, 59.7, 58.5–57.5 (br., 2 C) ppm. As further
proof of structure, a low-temperature NMR spectrum was recorded
to “freeze out” the vinylogous amide rotamers: 1H NMR
(400 MHz, CDCl3, 3 drops of CD3OD, –20 °C): δ = 8.00–8.03 (m,
2 H), 7.74 (d, J = 7.5 Hz, 1 H), 7.65 (d, J = 7.5 Hz, 1 H), 5.84 (d,
J = 20 Hz, 1 H), 5.67 (s, 1 H), 4.78 (d, J = 14.4 Hz, 2 H), 4.30–
4.19 (m, 5 H) ppm. 13C NMR (100 MHz, CDCl3, –20 °C): δ =
183.0, 182.8, 182.3, 147.9, 147.8, 141.0, 136.7, 134.3, 132.7, 132.01,
132.0, 131.1, 126.5, 126.5, 125.2, 121.2, 116.6, 104.0, 103.8, 58.8,
[M – Cl]+, 224 (42) [M – H – CH2Cl]+. HRMS (EI, 70 eV): calcd.
for C15H12ClNO2 [M]+ 273.0557; found 273.0556.
2-[2-(Acetoxymethyl)-2,5-dihydropyrrol-1-yl]-1,4-naphthoquinone
(38): Trifluoroacetic acid (123 µL, 1.6 mmol) was added to 12
(39.7 mg, 0.160 mmol) in CH2Cl2 (2 mL). After 2 h, the mixture
was concentrated and exposed to high vacuum for 1 h. The residue
was dissolved in THF (2 mL), and triethylamine (24.5 µL,
0.176 mmol) was added. After 10 min, this mixture was added to
1,4-naphthoquinone (25.3 mg, 0.160 mmol) and copper(I) bromide
(4.6 mg, 32 µmol) in THF (1 mL) in the dark. The mixture was
heated to reflux open to air in the dark. After 2 d, it was cooled to
room temp. and concentrated. The residue was chromatographed
(10 % to 40 % ethyl acetate/hexanes, gradient) to yield 23.6 mg
(50%) of the title compound. Rf = 0.05 (30% ethyl acetate/hex-
58.6, 58.4, 58.0, 57.5, 57.2 ppm. IR (neat): ν = 3364 (m, br.), 2918
˜
(m), 2849 (m), 1672 (m), 1608 (m), 1589 (s), 1539 (s), 1454 (m),
1420 (m) cm–1. UV (CHCl3): λmax = 247, 277, 464, 642, 729 nm
(logε= 3.91, 3.99, 3.53, 3.29, 3.21). LRMS (CI, NH3): m/z (%) =
256 (100), 238 (38), 225 (21). HRMS (CI, NH3): calcd. for
C15H14NO3 [M + H]+ 256.0974; found 256.0961. C15H13NO3
(255.09): calcd. C 70.58, H 5.13, N 5.49; found C 70.61, H 5.03, N
5.27.
anes). IR (neat): ν = 1741 (s), 1674 (m), 1626 (m), 1592 (m), 1557
˜
(s) cm–1
.
1H NMR (400 MHz, CDCl3): δ = 8.03 (dd, J = 7.5,
1.1 Hz, 1 H), 8.00 (dd, J = 7.7, 1.1 Hz, 1 H), 7.68 (td, J = 7.5,
2-[3-(Acetoxyoxymethyl)-2,5-dihydropyrrol-1-yl]-1,4-naphthoquinone 1.5 Hz, 1 H), 7.60 (td, J = 7.5, 1.5 Hz, 1 H), 6.02 (dd, J = 6.6,
(35): 2-[3-(Hydroxymethyl)-2,5-dihydropyrrol-1-yl]-1,4-naphtho- 1.8 Hz, 1 H), 5.88 (s, 1 H), 5.88–5.85 (m, 1 H), 5.51 (s, 1 H), 4.40
quinone (34) (0.0700 g, 0.275 mmol) was dissolved in pyridine (s, 1 H), 4.32–4.17 (m, 1 H), 4.31 (dd, J = 11.5, 2.9 Hz, 1 H), 4.19
(1 mL) in a flask wrapped in aluminum foil (to protect the contents
from light). The solution was cooled in an ice bath, and acetic
anhydride (0.2800 g, 2.77 mmol) was added. After 5 min, the bath
was removed and stirring continued for 4 h. The reaction mixture
was then diluted with EtOAc (ca. 10 mL) and aqueous NaOH
(10 mL of a 15% w/v solution). The layers were then separated,
(dd, J = 11.7, 4.4 Hz, 1 H), 1.97 (s, 3 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 183.39, 182.95, 170.74, 148.58, 134.35, 132.58, 131.80,
127.43, 126.73, 125.66, 106.53, 65.51, 63.62, 58.06, 20.62 ppm. MS
(EI, 70 eV): m/z (%) = 297 (6) [M]+, 237 (36) [M –HOAc]+, 224
(100) [M – CH2OAc]+. HRMS (EI, 70 eV): calcd. for C17H15NO4
[M]+ 297.1001; found 297.1006.
4272
www.eurjoc.org
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 4264–4276

2-(3-Pyrrolin-1-yl)-1,4-naphthoquinones: Photoactivated Alkylating Agents
2-[2-(Acetoxymethyl)-4-(chloromethyl)-2,5-dihydropyrrol-1-yl]-1,4- CDCl3): δ = 188.06, 182.16, 170.55, 161.88, 147.56, 137.13, 132.77,
naphthoquinone (39): Trifluoroacetic acid (0.185 mL, 2.40 mmol) 127.40, 126.07, 122.70, 118.03, 115.02, 107.98, 65.58, 63.97, 58.26,
was added to 13 (69.5 mg, 0.240 mmol) in CH2Cl2 (2.5 mL). After 29.67, 20.69 ppm. MS (EI, 70 eV): m/z (%) = 253 (46) [M –
3 h, the mixture was concentrated and exposed to high vacuum for
1 h. The residue was dissolved in THF (2.5 mL), and triethylamine
(36.8 µL, 0.264 mmol) was added. After 10 min, this mixture was
added to 1,4-naphthoquinone (37.9 mg, 0.240 mmol) and copper(I)
bromide (6.9 mg, 48 µmol) in THF (1 mL) in the dark. The mixture
was heated to reflux open to air in the dark. After 16 h, it was
cooled to room temp. and concentrated. The residue was chromato-
graphed (30% ethyl acetate/hexanes) to yield 28.2 mg (34%) of the
title compound. Rf = 0.25 (50% ethyl acetate/hexanes). IR (neat):
HOAc]+, 57 (100). HRMS (ESI): calcd. for C17H15NO5 [M +
Na]+ 336.0848; found 336.0849.
7-(2-Acetoxymethyl-2,5-dihydropyrrol-1-yl)isoquinoline-5,8-dione
(44): Trifluoroacetic acid (0.11 mL, 1.4 mmol) was added to 12
(33.8 mg, 0.140 mmol) in CH2Cl2 (2 mL). After 1 h, the mixture
was concentrated and exposed to high vacuum for 1 h. The residue
was dissolved in THF (2.5 mL), and triethylamine (22 µL,
0.15 mmol) was added. After 10 min, this mixture was added to
isoquinoline-5,8-dione (22.3 mg, 0.140 mmol) and copper(I) bro-
mide (4.0 mg, 28 µmol) in THF (1 mL) in the dark. The mixture
was heated to reflux open to air in the dark. After 16 h, it was
cooled to room temp. and concentrated. The residue was chromato-
graphed (30 % to 60 % ethyl acetate/hexanes, gradient) to yield
21.4 mg (51%) of the title compound. Rf = 0.13 (60% ethyl acetate/
ν = 1739 (s), 1670 (s), 1626 (m), 1592 (m), 1556 (s) cm–1. 1H NMR
˜
(300 MHz, CDCl3): δ = 8.05 (dd, J = 8.4, 1.5 Hz, 1 H), 8.02 (dd,
J = 7.6, 1.1 Hz, 1 H), 7.71 (td, J = 7.6, 1.4 Hz, 1 H), 7.63 (td, J =
7.6, 1.4 Hz, 1 H), 5.89 (s, 1 H), 5.87 (s, 1 H), 5.52 (s, 1 H), 4.52 (s,
1 H), 4.38 (dd, J = 11.5, 2.7 Hz, 1 H), 4.32–4.23 (m, 1 H), 4.23 (s,
2 H), 4.20 (dd, J = 11.7, 4.1 Hz, 1 H), 2.00 (s, 3 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 182.98, 179.85, 170.56, 147.86, 134.26,
132.53, 132.23, 131.76, 126.57, 125.57, 107.25, 96.18 94.50, 84.63,
65.96, 58.08, 39.56, 20.70 ppm. MS (EI, 70 eV): m/z (%) = 117 (97),
49 (100). HRMS (ESI): calcd. for C18H16ClNO4 [M + Na]+
368.0666; found 368.0663.
hexanes). IR (neat): ν = 1740 (s), 1679 (m), 1627 (s), 1586 (m), 1548
˜
1
(s) cm–1. H NMR (400 MHz, CDCl3): δ = 9.25 (s, 1 H), 8.98 (d,
J = 4.8 Hz, 1 H), 7.86 (d, J = 5.1 Hz, 1 H), 6.05 (dd, J = 6.6,
1.8 Hz, 1 H), 5.92–5.88 (m, 1 H), 5.91 (s, 1 H), 5.52 (s, 1 H), 4.40
(s, 1 H), 4.33–4.24 (m, 3 H), 1.99 (s, 3 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 182.49, 180.94, 170.49, 155.53, 153.96,
148.28, 147.98, 147.83, 138.15, 125.46, 118.09, 107.56, 65.61, 58.07,
29.66, 20.69 ppm. MS (EI, 70 eV): m/z (%) = 298 (3) [M]+, 238 (45)
[M – HOAc]+, 225 (100) [M – CH2OAc]+. HRMS (EI, 70 eV):
calcd. for C16H14N2O4 [M]+ 298.0954; found 298.0965.
2-[cis-2,5-Bis(acetoxymethyl)-2,5-dihydropyrrol-1-yl]-1,4-naphtho-
quinone (40): Trifluoroacetic acid (92 µL, 1.2 mmol) was added to
14 (39.0 mg, 0.120 mmol) in CH2Cl2 (1.5 mL). After 2.5 h, the mix-
ture was concentrated and exposed to high vacuum for 1 h. The
residue was dissolved in THF (1.5 mL), and triethylamine (19.5 µL,
0.140 mmol) was added. After 10 min, this mixture was added to
1,4-naphthoquinone (19.0 mg, 0.120 mmol) and copper(I) bromide
(3.4 mg, 24 µmol) in THF (1 mL) in the dark. The mixture was
heated to reflux open to air in the dark. After 3 d, it was cooled to
room temp. and concentrated. The residue was chromatographed
(10 % to 40 % ethyl acetate/hexanes, gradient) to yield 23.3 mg
(52%) of the title compound. Rf = 0.10 (30% ethyl acetate/hex-
7-[3-(Chloromethyl)-2,5-dihydropyrrol-1-yl]isoquinoline-5,8-dione
(45): Trifluoroacetic acid (0.41 mL, 5.3 mmol) was added to 10
(106 mg, 0.530 mmol) in CH2Cl2 (7.5 mL). After 2 h, the mixture
was concentrated and exposed to high vacuum for 1 h. The residue
was dissolved in THF (7.5 mL), and triethylamine (81 µL,
0.58 mmol) was added. After 10 min, this mixture was added to
isoquinoline-5,8-dione (84.3 mg, 0.530 mmol) and copper(I) bro-
mide (15.2 mg, 106 µmol) in THF (3 mL) in the dark. The mixture
was heated to reflux open to air in the dark. After 1.5 h, it was
cooled to room temp. and concentrated. The residue was chromato-
graphed (40 % to 65 % ethyl acetate/hexanes, gradient) to yield
80.5 mg (55%) of the title compound. Rf = 0.10 (50% ethyl acetate/
anes). IR (neat): ν = 1741 (s), 1674 (s), 1631 (m), 1592 (m), 1550
˜
(s) cm–1. 1H NMR (500 MHz, CDCl3): δ = 8.04 (td, J = 7.6, 1.0 Hz,
2 H), 7.72 (td, J = 7.6, 1.5 Hz, 1 H), 7.64 (td, J = 7.6, 1.5 Hz, 1
H), 6.09 (s, 1 H), 6.00 (s, 2 H), 5.19 (dd, J = 5.2, 3.7 Hz, 2 H), 4.47
(dd, J = 11.3, 3.7 Hz, 2 H), 4.24 (dd, J = 11.2, 5.9 Hz, 2 H), 2.11
(s, 6 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 183.41, 170.70,
148.00, 134.27, 132.37, 132.14, 128.42, 126.76, 125.44, 107.29,
66.56, 64.39, 20.77 ppm. MS (EI, 70 eV): m/z (%) = 236 (100) [M –
HOAc – CH2OAc]+. HRMS (ESI): calcd. for C20H19NO6 [M +
Na]+ 392.1110; found 392.1100.
hexanes). IR (neat): ν = 1676 (m), 1631 (m), 1586 (m), 1554 (s)
˜
1
cm–1. H NMR (500 MHz, CDCl3): δ = 9.27 (s, 1 H), 9.00 (d, J =
4.9 Hz, 1 H), 7.89 (dd, J = 4.9, 0.7 Hz, 1 H), 6.00 (s, 1 H), 5.82 (s,
1 H), 4.90 (s, 1 H), 4.25 (s, 4 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 180.43, 155.53, 153.78, 148.15, 138.44, 125.11, 121.16,
118.09, 118.03, 105.74, 58.16, 57.56, 39.68 ppm. MS (EI, 70 eV):
m/z (%) = 274 (53) [M]+, 239 (100) [M – Cl]+, 225 (56) [M –
CH2Cl]+. HRMS (EI, 70 eV): calcd. for C14H11ClN2O2 [M]+
274.0509; found 274.0504.
2-(2-Acetoxymethyl-2,5-dihydropyrrol-1-yl)-8-hydroxy-1,4-naphtho-
quinone (42): Trifluoroacetic acid (97 µL, 1.3 mmol) was added to
12 (30.5 mg, 0.126 mmol) in CH2Cl2 (2 mL). After 1.5 h, the mix-
ture was concentrated and exposed to high vacuum for 1 h. The
residue was dissolved in THF (2 mL), and triethylamine (19.3 µL,
0.139 mmol) was added. After 10 min, this mixture was added to
6-[2-(Acetoxymethyl)-2,5-dihydropyrrol-1-yl]quinoline-5,8-dione
(46): Trifluoroacetic acid (0.16 mL, 2.1 mmol) was added to 12
juglone (21.9 mg, 0.126 mmol) and copper(I) bromide (3.6 mg, (50.7 mg, 0.210 mmol) in CH2Cl2 (2 mL). After 3 h, the mixture
25 µmol) in THF (1 mL) in the dark. The mixture was heated to
reflux open to air in the dark. After 2 d, it was cooled to room
temp. and concentrated. The residue was chromatographed (10%
to 40% ethyl acetate/hexanes, gradient) to yield 17.7 mg (45%) of
was concentrated and exposed to high vacuum for 1 h. The residue
was dissolved in THF (1 mL), and triethylamine (32 µL,
0.23 mmol) was added. After 10 min, this mixture was added to
quinoline-5,8-dione (33.4 mg, 0.210 mmol) and cerium(III) chlo-
ride heptahydrate (78.2 mg, 0.210 mmol) in ethanol (4 mL) in the
dark. After stirring for 18 h open to air in the dark, water was
the title compound. Rf = 0.09 (40% ethyl acetate/hexanes). IR
1
(neat): ν = 1740 (s), 1625 (s), 1557 (s) cm–1. H NMR (400 MHz,
˜
CDCl3): δ = 11.84 (s, 1 H), 7.56 (d, J = 5.1 Hz, 1 H), 7.55 (d, J = added, and the mixture was extracted with ethyl acetate (5ϫ), dried
4.0 Hz, 1 H), 7.12 (t, J = 4.8 Hz, 1 H), 6.01 (dd, J = 6.6, 1.8 Hz, 1
H), 5.85 (dd, J = 6.6, 2.2 Hz, 1 H), 5.79 (s, 1 H), 5.47 (s, 1 H), 4.38
(s, 1 H), 4.28 (dd, J = 11.5, 3.3 Hz, 1 H), 4.23–4.18 (m, 1 H), 4.19
(Na2SO4) and concentrated. The residue was chromatographed
(0 % to 5 % methanol/ethyl acetate, gradient) to yield 33.2 mg
(53%) of the title compound. Rf = 0.18 (5% methanol/ethyl ace-
(dd, J = 11.4, 4.4 Hz, 1 H), 1.96 (s, 3 H) ppm. 13C NMR (100 MHz, tate). IR (neat): ν = 1738 (s), 1683 (m), 1627 (m), 1552 (s) cm–1.
˜
Eur. J. Org. Chem. 2008, 4264–4276
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4273

A. Aponick, A. L. Dietz, W. H. Pearson
FULL PAPER
1H NMR (400 MHz, CDCl3): δ = 9.01 (d, J = 3.7 Hz, 1 H), 8.36
(dd, J = 8.0, 1.5 Hz, 1 H), 7.60 (dd, J = 7.7, 4.8 Hz, 1 H), 6.05 (s,
1 H), 6.04 (dd, J = 6.6, 1.8 Hz, 1 H), 5.88 (dd, J = 6.6, 2.2 Hz, 1
dissolved in THF (1.5 mL), and triethylamine (44.6 µL, 0.32 mmol)
was added. After 10 min, this mixture was added to quinoline-5,8-
dione (46.8 mg, 0.290 mmol) and cerium(III) chloride heptahydrate
H), 5.58 (s, 1 H), 4.42 (s, 1 H), 4.32–4.22 (m, 1 H), 4.30 (dd, J = (0.108 g, 0.290 mmol) in ethanol (6 mL) in the dark. After stirring
11.5, 2.9 Hz, 1 H), 4.24 (dd, J = 11.7, 4.0 Hz, 1 H), 1.98 (s, 3 H) for 2 d open to air in the dark, water and brine were added, and
ppm. 13C NMR (100 MHz, CDCl3): δ = 182.04, 181.48, 170.89, the mixture was extracted with ethyl acetate (4ϫ), dried (Na2SO4)
154.40, 148.43, 148.08, 135.05, 128.27, 126.79, 125.86, 106.98, and concentrated. The residue was chromatographed (0% to 5%
65.75, 63.54, 58.22, 20.28 ppm. MS (EI, 70 eV): m/z (%) = 298 (1) methanol/ethyl acetate, gradient) to yield 40.6 mg (38%) of the title
[M]+ , 238 (100) [M – HOAc]+ . HRMS (ESI): calcd. for
compound. R = 0.20 (5% methanol/ethyl acetate). IR (neat): ν =
˜
f
C16H14N2O4 [M + Na]+ 321.0851; found 321.0846.
1742 (s), 1684 (s), 1547 (s) cm–1. 1H NMR (400 MHz, CDCl3): δ =
8.98 (dd, J = 4.8, 1.5 Hz, 1 H), 8.34 (dd, J = 7.9, 1.5 Hz, 1 H), 7.58
(dd, J = 8.0, 4.8 Hz, 1 H), 6.25 (s, 1 H), 5.99 (s, 1 H), 5.79 (s, 1 H),
5.16 (t, J = 3.7 Hz, 1 H), 4.43 (dd, J = 11.3, 3.7 Hz, 1 H), 4.36 (t,
J = 4.8 Hz, 1 H), 4.23 (dd, J = 11.3, 5.9 Hz, 1 H), 4.00 (dd, J =
9.5, 5.3 Hz, 1 H), 2.09 (s, 3 H), 2.05 (s, 3 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 181.85, 171.18, 170.66, 154.84, 147.67,
135.13, 128.28, 127.76, 126.88, 107.72, 93.99, 66.87, 64.97, 64.05,
62.53, 20.71, 20.37 ppm. MS (EI, 70 eV): m/z (%) = 252 (100) [M –
2 OAc]+. HRMS (ESI): calcd. for C19H18N2O6 [M + Na]+
393.1063; found 393.1068.
6-[3-(Chloromethyl)-2,5-dihydropyrrol-1-yl]quinoline-5,8-dione (47):
Trifluoroacetic acid (0.146 mL, 1.9 mmol) was added to 10
(41.4 mg, 0.190 mmol) in CH2Cl2 (2 mL). After 1.5 h, the mixture
was concentrated and exposed to high vacuum for 1 h. The residue
was dissolved in THF (1 mL), and triethylamine (29.3 µL,
0.21 mmol) was added. After 10 min, this mixture was added to
quinoline-5,8-dione (30.4 mg, 0.190 mmol) and cerium(III) chlo-
ride heptahydrate (70.8 mg, 0.190 mmol) in ethanol (4 mL) in the
dark. After stirring for 16 h open to air in the dark, water was
added, and the mixture was extracted with ethyl acetate (4ϫ), dried
(Na2SO4) and concentrated. The residue was chromatographed
(0 % to 5 % methanol/ethyl acetate, gradient) to yield 38.2 mg
(73%) of the title compound. Rf = 0.14 (5% methanol/ethyl ace-
2-[3-(Hydroxymethyl)pyrrol-1-yl]-1,4-naphthoquinone (52): An
NMR sample of the pyrroline 34 in CDCl3 was allowed to stand
under ambient laboratory light until the starting material was con-
tate). IR (neat): ν = 1682 (s), 1623 (s), 1555 (s) cm–1. 1H NMR sumed (approximately 3 d): Rf = 0.17 (30% acetone/hexanes). 1H
˜
(400 MHz, CDCl3): δ = 8.98 (dd, J = 4.6, 1.5 Hz, 1 H), 8.32 (dd,
J = 8.0, 1.5 Hz, 1 H), 7.55 (dd, J = 8.0, 4.8 Hz, 1 H), 5.92 (s, 2 H),
4.81 (s, 2 H), 4.20 (s, 4 H) ppm. 13C NMR (100 MHz, CDCl3): δ
= 182.18, 181.05, 154.85, 148.77, 147.56, 134.62, 128.10, 126.32,
106.32, 57.87, 39.58 ppm. MS (EI, 70 eV): m/z (%) = 274 (41)
[M]+, 239 (100) [M – Cl]+, 225 (58) [M – CH2Cl]+. HRMS (EI,
70 eV): calcd. for C14H11ClN2O2 [M]+ 274.0509; found 274.0500.
NMR (CDCl3, 500 MHz): δ = 8.20–8.11 (m, 2 H), 7.83–7.76 (m, 2
H), 7.31–7.29 (m, 1 H), 7.27–7.25 (m, 1 H), 6.82 (s, 1 H), 6.46–6.45
(m, 1 H), 4.63 (s, 2 H), 1.25 (s, 1 H) ppm. 13C NMR (CDCl3,
125 MHz): δ = 184.4, 181.1, 142.7, 134.5, 133.9, 131.5, 131.7, 128.9,
127.2, 126.1, 122.5, 122.4, 119.6, 112.6, 58.6 ppm. UV (CHCl3):
λmax = 257, 307, 643, 400 nm (log ε = 4.17, 3.90, 3.45, 3.69).
2-{3-[(Ethylsulfanyl)methyl]pyrrol-1-yl}-1,4-naphthoquinone (53):
6-[2-(Acetoxymethyl)-4-(chloromethyl)-2,5-dihydropyrrol-1-yl]quino-
Ethanethiol (24 µL, 0.32 mmol) was added to 36 (8.80 mg,
line-5,8-dione (48): Trifluoroacetic acid (0.205 mL, 2.7 mmol) was 32.0 µmol) and 2,6-lutidine (3.7 µL, 32 µmol) in chloroform
added to 13 (77.0 mg, 0.266 mmol) in CH2Cl2 (3 mL). After 2.5 h,
(2 mL). After being exposed to ambient light and open to air for
the mixture was concentrated and exposed to high vacuum for 1 h.
2 d, there was no 36 remaining so the mixture was adsorbed on
The residue was dissolved in THF (1.5 mL), and triethylamine silica gel, while the solvent was removed in a rotavapor, and chro-
(40.7 µL, 0.292 mmol) was added. After 10 min, this mixture was
added to quinoline-5,8-dione (42.3 mg, 0.266 mmol) and ce-
rium(III) chloride heptahydrate (99.1 µg, 0.266 mmol) in ethanol
(5 mL) in the dark. After stirring for 16 h open to air in the dark,
the mixture was diluted with ethyl acetate and washed with brine.
The aqueous layer was extracted with ethyl acetate, and the com-
bined organic layers were dried (Na2SO4) and concentrated. The
residue was chromatographed (0% to 5% methanol/ethyl acetate,
gradient) to yield 49.9 mg (54%) of the title compound. Rf = 0.19
matographed (10% to 20% ethyl acetate/hexanes, gradient) to yield
6.0 mg (63%) of the title compound. Rf = 0.34 (20% ethyl acetate/
hexanes). IR (neat): ν = 1679 (s), 1646 (s) cm–1 1H NMR
.
˜
(400 MHz, CDCl3): δ = 8.14–8.12 (m, 1 H), 8.08–8.06 (m, 1 H),
7.76–7.73 (m, 2 H), 7.24 (s, 1 H), 7.19 (s, 1 H), 6.76 (s, 1 H), 6.36
(s, 1 H), 3.61 (s, 2 H), 2.48 (q, J = 7.3 Hz, 2 H), 1.23 (t, J = 7.3 Hz,
3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 184.41, 181.05,
142.58, 134.40, 133.80, 131.98, 131.52, 127.16, 126.01, 125.38,
122.30, 121.91, 119.65, 113.77, 27.70, 25.38, 14.40 ppm. MS (EI,
70 eV): m/z (%) = 297 (17) [M]+, 236 (100) [M – SEt]+. HRMS (EI,
(5% methanol/ethyl acetate). IR (neat): ν = 1738 (s), 1683 (s), 1627
˜
1
(m), 1552 (s) cm–1. H NMR (400 MHz, CDCl3): δ = 8.98 (d, J = 70 eV): calcd. for C17H15NO2S [M – H]+ 296.0745; found 296.0747.
3.7 Hz, 1 H), 8.33 (dd, J = 7.9, 1.5 Hz, 1 H), 7.56 (dd, J = 8.0,
4.8 Hz, 1 H), 6.03 (s, 1 H), 5.87 (s, 1 H), 5.48 (s, 1 H), 4.54 (s, 1
2-{2-[(Ethylsulfanyl)methyl]pyrrol-1-yl}-1,4-naphthoquinone (55):
Ethanethiol (26 µL, 0.35 mmol) was added to 38 (10.3 mg,
H), 4.52–4.17 (m, 1 H), 4.32 (dd, J = 11.5, 2.9 Hz, 1 H), 4.23 (dd,
35.0 µmol) in chloroform (3 mL). After being exposed to ambient
J = 11.7, 4.4 Hz, 1 H), 4.20 (s, 2 H), 1.98 (s, 3 H) ppm. 13C NMR
light and open to air for 24 h, there was no 38 remaining so the
(100 MHz, CDCl3): δ = 183.12, 181.96, 171.12, 155.47, 148.92,
mixture was adsorbed on silica gel, while the solvent was removed
148.18, 135.30 129.00, 127.08, 126.07, 108.74, 66.80, 64.00, 58.79,
in a rotavapor, and chromatographed (10% to 20% ethyl acetate/
hexanes, gradient) to yield a mixture of quinone and hydroquinone
39.90, 21.07 ppm. MS (EI, 70 eV): m/z (%) = 237 (59) [M – H –
CH2OAc – Cl]+, 43 (100) [COCH3]+. HRMS (ESI): calcd. for
products. The mixture was dissolved in CH2Cl2, and silica gel was
C17H15ClN2O4 [M + Na]+ 369.0618; found 369.0607.
added. After stirring for 2 h, the only product present was the qui-
6-[cis-2,5-Bis(acetoxymethyl)-2,5-dihydropyrrol-1-yl]quinoline-5,8-di- none product. Filtration and concentration yielded 9.0 mg (86%)
one (49): Trifluoroacetic acid (0.223 mL, 2.9 mmol) was added to
14 (92.1 mg, 0.290 mmol) in CH2Cl2 (3 mL). After 2.5 h, the reac-
tion was not complete, so an additional portion of trifluoroacetic
of the title compound. Rf = 0.22 (10% ethyl acetate/hexanes). IR
1
(neat): ν = 1678 (s), 1659 (s), 1280 (s) cm–1. H NMR (400 MHz,
˜
CDCl3): δ = 8.16 (dd, J = 5.8, 3.5 Hz, 1 H), 8.12 (dd, J = 5.6,
acid (50 µL, 0.65 mmol) was added. After 3 h, the mixture was con- 3.5 Hz, 1 H), 7.78 (dd, J = 5.1, 4.0 Hz, 2 H), 6.85 (s, 1 H), 6.78
centrated and exposed to high vacuum for 1 h. The residue was (dd, J = 2.9, 1.8 Hz, 1 H), 6.24–6.21 (m, 2 H), 3.78 (s, 2 H), 2.20
4274
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© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 4264–4276

2-(3-Pyrrolin-1-yl)-1,4-naphthoquinones: Photoactivated Alkylating Agents
(q, J = 7.3 Hz, 2 H), 1.06 (t, J = 7.3 Hz, 3 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 184.85, 180.23, 145.94, 134.22, 134.04,
2 d, there was no 39 remaining so the mixture was adsorbed on
silica gel, while the solvent was removed in a rotavapor, and chro-
131.98, 130.00, 127.91, 127.21, 126.33, 123.88, 121.98, 113.34, matographed (10% to 20% ethyl acetate/hexanes, gradient) to yield
109.96, 28.04, 25.01, 13.95 ppm. MS (EI, 70 eV): m/z (%) = 297 45.2 mg (76%) of the title compound. Although characterized as
(15) [M]+, 236 (100) [M – SEt]+. HRMS (EI, 70 eV): calcd. for the hydroquinone, this compound was found to be relatively un-
C17H15NO2S [M]+ 297.0824; found 297.0833.
stable, converting over time to the quinone product. Rf = 0.38 (30%
ethyl acetate/hexanes). IR (neat): ν = 3388 (br.) cm–1. 1H NMR
˜
6-{3-[(Ethylsulfanyl)methyl]pyrrol-1-yl}quinoline-5,8-diol (56): Eth-
anethiol (52 µL, 0.70 mmol) was added to 47 (19.3 mg, 70.0 µmol)
and 2,6-lutidine (8.2 µL, 70 µmol) in chloroform (3.5 mL). After
being exposed to ambient light and open to air for 18 h, there was
no 47 remaining so the mixture was adsorbed on silica gel, while
the solvent was removed in a rotavapor, and chromatographed
(20% to 30% ethyl acetate/hexanes, gradient) to yield 8.8 mg (42%)
(300 MHz, CDCl3): δ = 8.28 (dd, J = 6.2, 3.3 Hz, 1 H), 8.16 (dd,
J = 5.9, 3.3 Hz, 1 H), 7.58 (dd, J = 6.3, 3.3 Hz, 2 H), 6.64 (s, 2 H),
6.23 (s, 1 H), 5.77 (s, 2 H), 3.65 (s, 4 H), 2.55 (q, J = 7.4 Hz, 2 H),
2.45 (q, J = 7.4 Hz, 2 H), 1.27 (t, J = 7.4 Hz, 3 H), 1.15 (t, J =
7.4 Hz, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 145.10,
141.97, 130.88, 126.64, 126.60, 125.93, 125.35, 122.98, 121.88,
121.68, 121.40, 119.69, 110.25, 108.60, 27.87, 26.63, 25.61, 25.49,
14.43, 14.10 ppm. MS (EI, 70 eV): m/z (%) = 311 (63) [M –
HSEt]+, 250 (100) [M – HSEt – SEt]+. HRMS (ESI): calcd. for
C20H23NO2S2 [M + Na]+ 396.1068; found 396.1068.
of the title compound. Rf = 0.19 (20% ethyl acetate/hexanes). IR
1
(neat): ν = 3390 (br.) cm–1. H NMR (300 MHz, CDCl ): δ = 8.81
˜
3
(dd, J = 4.4, 1.3 Hz, 1 H), 8.58 (dd, J = 7.8, 1.3 Hz, 1 H), 7.50 (dd,
J = 8.5, 4.4 Hz, 1 H), 7.05 (s, 1 H), 6.88–6.87 (m, 2 H), 6.41 (t, J
= 1.9 Hz, 1 H), 3.72 (s, 2 H), 2.57 (q, J = 7.4 Hz, 2 H), 1.29 (t, J
= 7.4 Hz, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 148.59,
146.17, 137.44, 131.88, 123.44, 122.71, 122.18, 121.73, 120.10,
111.64, 107.89, 29.62, 27.80, 25.63, 14.38 ppm. MS (EI, 70 eV): m/z
(%) = 239 (100) [M – SEt]+, 238 (99) [M – HSEt]+. HRMS (ESI):
calcd. for C16H16N2O2S [M + H]+ 301.1011; found 301.1010.
2-{2,5-Bis[(ethylsulfanyl)methyl]pyrrol-1-yl}naphthalene-1,4-diol
(60): Ethanethiol (47 µL, 0.63 mmol) was added to 40 (23.3 mg,
63.0 µmol) in chloroform (3 mL). After being exposed to ambient
light and open to air for 2 d, there was no starting material remain-
ing so the mixture was adsorbed onto silica gel and chromato-
graphed (10% to 20% ethyl acetate/hexanes, gradient) to yield
19.0 mg (81%) of the title compound. Rf = 0.29 (20% ethyl acetate/
6-{2-[(Ethylsulfanyl)methyl]pyrrol-1-yl}quinoline-5,8-diol (57): Eth-
anethiol (21 µL, 0.28 mmol) was added to 46 (8.4 mg, 28 µmol) in
chloroform (3 mL). After being exposed to ambient light and open
to air for 16 h, there was no 46 remaining so the mixture was ad-
sorbed on silica gel, while the solvent was removed in a rotavapor,
and chromatographed (20% ethyl acetate/hexanes) to yield 5.6 mg
(67%) of the title compound. Rf = 0.25 (30% ethyl acetate/hex-
hexanes). IR (neat): ν = 3391 (br.), 1598 (s) cm–1. 1H NMR
˜
(400 MHz, CDCl3): δ = 8.32–8.29 (m, 1 H), 8.18–8.15 (m, 1 H),
7.57 (td, J = 4.9, 1.5 Hz, 2 H), 6.60 (s, 1 H), 6.15 (s, 2 H), 5.80 (s,
1 H), 5.32 (s, 1 H), 3.44 (d, J = 2.9 Hz, 4 H), 2.40 (q, J = 7.3 Hz,
4 H), 1.11 (t, J = 7.3 Hz, 6 H) ppm. 13C NMR (100 MHz, CDCl3):
δ = 145.28, 142.92, 130.98, 126.77, 126.60, 125.70, 123.24, 121.69,
118.27, 109.43, 108.70, 27.10, 25.50, 14.16 ppm. MS (EI, 70 eV):
m/z (%) = 311 (66) [M – HSEt]+, 250 (100) [M – HSEt – SEt]+.
HRMS (ESI): calcd. for C20H23NO2S2 [M + Na]+ 396.1068; found
396.1082.
anes). IR (neat): ν = 3398 (br.) cm–1. 1H NMR (300 MHz, CDCl ):
˜
3
δ = 8.85 (dd, J = 4.2, 1.6 Hz, 1 H), 8.64 (dd, J = 8.4, 1.6 Hz, 1 H),
7.88 (s, 1 H), 7.52 (dd, J = 8.5, 4.1 Hz, 1 H), 6.97 (s, 1 H), 6.75
(dd, J = 2.7, 1.9 Hz, 1 H), 6.30 (dd, J = 3.6, 2.7 Hz, 1 H), 6.26 (dd,
J = 3.6, 1.6 Hz, 1 H), 5.97 (s, 1 H), 3.64 (s, 1 H), 3.52 (s, 1 H), 2.45
(q, J = 7.4 Hz, 2 H), 1.16 (t, J = 7.4 Hz, 3 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 149.03, 146.24, 140.19, 138.49, 132.36,
130.37, 123.55, 122.02, 121.70, 120.80, 110.00, 109.83, 109.52,
26.85, 25.50, 14.12 ppm. MS (EI, 70 eV): m/z (%) = 238 (100) [M –
HSEt]+. HRMS (ESI): calcd. for C16H16N2O2S [M + H]+ 301.1011;
found 301.1008.
6-{2,4-Bis[(ethylsulfanyl)methyl]pyrrol-1-yl}quinoline-5,8-diol (61):
Ethanethiol (47 µL, 0.64 mmol) was added to 48 (22.3 mg,
64.0 µmol) in chloroform (3 mL). After being exposed to ambient
light and open to air for 18 h, there was no 48 remaining so the
mixture was adsorbed on silica gel, while the solvent was removed
in a rotavapor, and chromatographed (20% to 30% ethyl acetate/
hexanes, gradient) to yield 10.6 mg (44%) of the title compound.
R = 0.14 (20% ethyl acetate/hexanes). IR (neat): ν = 3390 (br.)
˜
2-{2-[(Ethylsulfanyl)methyl]pyrrol-1-yl}-8-hydroxy-1,4-naphthoquin-
one (58): Ethanethiol (24 µL, 0.32 mmol) was added to 42 (10.2 mg,
32.0 µmol) in chloroform (1.6 mL). After being exposed to ambient
light and open to air for 2 d, there was no 42 remaining so the
mixture was adsorbed on silica gel, while the solvent was removed
in a rotavapor, and chromatographed (10% to 20% ethyl acetate/
hexanes, gradient) to yield 4.4 mg (44%) of the title compound. Rf
f
cm–1. H NMR (300 MHz, CDCl3): δ = 8.85 (dd, J = 4.1, 1.4 Hz,
1 H), 8.63 (dd, J = 8.5, 1.4 Hz, 1 H), 7.87 (s, 1 H), 7.52 (dd, J =
8.5, 4.1 Hz, 1 H), 6.95 (s, 1 H), 6.66 (d, J = 1.6 Hz, 1 H), 6.24 (d,
J = 1.6 Hz, 1 H), 6.02 (s, 1 H), 3.66 (s, 4 H), 2.55 (q, J = 7.4 Hz,
2 H), 2.46 (q, J = 7.4 Hz, 2 H), 1.27 (t, J = 7.4 Hz, 3 H), 1.16 (t,
J = 7.4 Hz, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 149.03,
146.26, 140.16, 138.48, 132.35, 130.94, 121.99, 121.86, 121.72,
120.82, 110.62, 109.79, 27.97, 26.88, 25.64, 25.55, 14.46, 14.14 ppm.
MS (EI, 70 eV): m/z (%) = 312 (53) [M – HSEt]+, 251 (100) [M –
HSEt – SEt]+. HRMS (ESI): calcd. for C19H22N2O2S2 [M + H]+
375.1201; found 375.1199.
1
= 0.47 (30% ethyl acetate/hexanes). IR (neat): ν = 1642 (s), 1606
˜
(s), 1277 (s) cm–1. 1H NMR (400 MHz, CDCl3): δ = 11.73 (s, 1 H),
7.65 (d, J = 4.4 Hz, 2 H), 7.29 (t, J = 4.8 Hz, 1 H), 6.85 (s, 1 H),
6.75 (t, J = 2.9 Hz, 1 H), 6.22–6.20 (m, 2 H), 3.76 (s, 2 H), 2.20 (q, J
= 7.3 Hz, 2 H), 1.05 (t, J = 7.3 Hz, 3 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 184.58, 162.76, 137.71, 132.71, 131.70, 130.58, 125.35,
124.73, 119.89, 115.34, 113.79, 110.52, 94.62, 28.42, 25.57,
14.60 ppm. MS (EI, 70 eV): m/z (%) = 313 (19) [M]+, 252 (100)
[M – SEt]+. HRMS (EI, 70 eV): calcd. for C17H15NO3S [M]+
313.0773; found 313.0775.
6-{2,5-Bis[(ethylsulfanyl)methyl]pyrrol-1-yl}quinoline-5,8-diol (62):
Ethanethiol (17 µL, 0.23 mmol) was added to 49 (8.5 mg, 23 µmol)
in chloroform (1 mL). After being exposed to ambient light and
open to air for 16 h, there was no 49 remaining so the mixture was
adsorbed on silica gel, while the solvent was removed in a rotav-
apor, and chromatographed (50% ethyl acetate/hexanes) to yield
2.6 mg (30%) of the title compound. Rf = 0.17 (30% ethyl acetate/
2-{2,4-Bis[(ethylsulfanyl)methyl]pyrrol-1-yl}naphthalene-1,4-diol
(59): Ethanethiol (120 µL, 1.6 mmol) was added to 39 (53.8 mg,
160 µmol) and 2,6-lutidine (18 µL, 0.16 mmol) in acetonitrile
(8 mL). After being exposed to ambient light and open to air for
hexanes). IR (neat): ν = 3392 (br.) cm–1. 1H NMR (400 MHz,
˜
CDCl3): δ = 8.86 (dd, J = 4.4, 1.5 Hz, 1 H), 8.69 (dd, J = 8.4,
Eur. J. Org. Chem. 2008, 4264–4276
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4275

A. Aponick, A. L. Dietz, W. H. Pearson
FULL PAPER
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1.5 Hz, 1 H), 7.54 (dd, J = 8.4, 4.4 Hz, 1 H), 6.95 (s, 1 H), 6.16 (s,
2 H), 6.06 (s, 1 H), 3.52 (d, J = 14.6 Hz, 2 H), 3.40 (d, J = 14.3 Hz,
2 H), 2.41 (q, J = 7.3 Hz, 4 H), 1.11 (t, J = 7.3 Hz, 6 H) ppm. 13C
NMR (100 MHz, CDCl3): δ = 148.73, 146.15, 142.50, 141.10,
133.29, 131.03, 121.94, 121.63, 120.81, 111.26, 108.95, 27.14, 25.39,
14.16 ppm. MS (EI, 70 eV): m/z (%) = 312 (32) [M – HSEt]+, 251
(100) [M – HSEt – SEt]+. HRMS (ESI): calcd. for C19H22N2O2S2
[M + H]+ 375.1201; found 375.1184.
Supporting Information (see footnote on the first page of this arti-
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Received: May 16, 2008
Published Online: July 9, 2008
4276
www.eurjoc.org
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 4264–4276