Arsenous chloride-free synthesis of cyclic tertiary organoarsines from arylarsine oxides and di-Grignard reagents

Article abstract of DOI:10.1016/j.jorganchem.2015.03.006

Abstract The growing importance of triarylarsines as ligands for transition metal catalysis has sparked recent interest in new synthetic routes to tertiary arsines that avoid hazardous arsenous chloride reagents. However, safer methods for the synthesis o

Full text of DOI:10.1016/j.jorganchem.2015.03.006

Journal of Organometallic Chemistry 785 (2015) 77e83
Contents lists available at ScienceDirect
Journal of Organometallic Chemistry
journal homepage: www.elsevier.com/locate/jorganchem
Arsenous chloride-free synthesis of cyclic tertiary organoarsines from
arylarsine oxides and di-Grignard reagents
Aaron M. Gregson, Steven M. Wales, Stephen J. Bailey, Paul A. Keller*
School of Chemistry, University of Wollongong, Wollongong, NSW 2522, Australia
a r t i c l e i n f o
a b s t r a c t
Article history:
The growing importance of triarylarsines as ligands for transition metal catalysis has sparked recent
interest in new synthetic routes to tertiary arsines that avoid hazardous arsenous chloride reagents.
However, safer methods for the synthesis of lesser explored arsine heterocycles, especially those con-
taining AseC(sp3) bonds, remain lacking. We demonstrate for the first time that bench stable, less
hazardous, arylarsine(III) oxides are effective substitutes for their corresponding chlorides in the one-pot
construction of cyclic tertiary organoarsines from di-Grignard reagents. Several known and novel het-
erocycles have been prepared in reasonable yields, accommodating variations in both the dio-
rganomagnesium reagent and electrophile, making this a modular approach to cyclic arsine assembly.
© 2015 Elsevier B.V. All rights reserved.
Received 31 January 2015
Received in revised form
25 February 2015
Accepted 5 March 2015
Available online 17 March 2015
Keywords:
Arsine oxides
Grignard reagents
Heterocycles
Organoarsines
Ligands
Introduction
the construction of acyclic triarylarsines via AseC(sp2) cross-
coupling [4d,9].
Organoarsines have found application in coordination chemis-
try [1], materials science [2] and recently in chemotherapy as po-
tential drug delivery and anti-cancer agents [3]. Triaryl arsines in
particular are now well established as valuable ligands for transi-
tion metal catalysis, demonstrating superiority to analogous
phosphines in many cases [4]. Although tertiary organoarsines are
traditionally prepared via the combination of arsenic chlorides (or
other halides) with organometallic reagents or nucleophilic arenes,
a major drawback to this approach is the inherent toxicity associ-
ated with the AseCl bond [5]. It is well known that arsenic com-
pounds (or metabolites thereof) generally exhibit toxicity [6],
however, most arsenous chlorides are additionally characterized by
alarming acute effects based on their rapid in vivo covalent binding
to thiol-containing enzymes and proteins [7]. These hazards are
exacerbated by the often semi-volatility of arsenous(III) chlorides,
which have historically been exploited as blistering and vomiting
agents in chemical warfare (e.g., Lewisite, Ph2AsCl, PhAsCl2 and
Adamsite) [5]. As such, tertiary organoarsine syntheses that avoid
this reagent class have received some interest [8], particularly for
In our own search for alternate methods of AseC bond forma-
tion, we turned our attention to seminal work by Blicke with ary-
larsine(III) oxides 1 (Scheme 1) [10]. In contrast to the noxious
arsenous chlorides, oxides 1 are generally bench-stable, non-hy-
groscopic solids that can be safely handled in the laboratory and are
resistant to atmospheric oxidation [11]. These compounds (arsen-
ous acid anhydrides) were shown to react with aryl Grignard re-
agents at ambient temperature to yield dimers 2 after addition of
the carbanion (Scheme 1a) [10a]. Attempts to achieve a second
Grignard addition were carried out with phenylarsine oxide 3 at
elevated temperature (Scheme 1b) [10a]. In the two examples re-
ported (both shown), the product ratio was highly dependent on
the concentration of the Grignard regent: a large excess (8 equiv)
was required to favour the second addition, enabling tripheny-
larsine to be obtained in near quantitative yield.
Although anhydrous arylarsine oxides are often depicted as
containing a
p-bond (As]O), spectroscopic experiments have
shown their existence in solid state and solution as well-defined
oligomers: (ArAsO)x [12]. Thus, the formation of a tertiary orga-
noarsine from 1 (or 3) likely involves the sequential cleavage of two
AseO s-bonds. In this way, arsine oxides could be considered as
direct synthetic equivalents of arsenous chlorides.
Encouraged by these findings, we became interested in inves-
tigating arsine oxides as safer substitutes for arsenous chlorides in
* Corresponding author. Tel.: þ61 2 4221 4692.
E-mail address: keller@uow.edu.au (P.A. Keller).
http://dx.doi.org/10.1016/j.jorganchem.2015.03.006
0022-328X/© 2015 Elsevier B.V. All rights reserved.

78
A.M. Gregson et al. / Journal of Organometallic Chemistry 785 (2015) 77e83
Table 1
Reaction optimization for the synthesis of arsolane 10 and arsinane 11 from (PhA-
sO)x.
Entry [Ref.]
n
Equiv Grignard Electrophile Temp (ꢁC) Product Yield (%)a
1 [15]
2 [16]
3 [17]
4 [18]
5 [19]
6 [17]
7
8
9
10
11
1
1
1
2
2
2
1
1
1
1
1
1
2
2
1.0
1.1
3.2
1.3
1.4
3.2
1.0
1.0
1.0
1.0
3.0
5.0
5.0
5.0
PhAsCl2
PhAsCl2
PhAsCl2
PhAsCl2
PhAsCl2
PhAsCl2
(PhAsO)x
(PhAsO)x
(PhAsO)x
(PhAsO)x
(PhAsO)x
(PhAsO)x
(PhAsO)x
(PhAsO)x
rt-refluxb 10
18
28
66
32
31
53
12
13
4
10
39d
42
9
10-rt
10-rt
10
10
Scheme 1. Previous organoarsine syntheses using arylarsine oxides as electrophiles
[10a].
rt-refluxb 11
0-rtb
10-rt
0-rt
11
11
10
10
the preparation of (semi)saturated arsine heterocycles 7 from di-
Grignard reagents (Scheme 2). Analogous cyclic phosphines and
their derived dimers have proven highly effective in ligand-assisted
catalysis and asymmetric variants [13], and thus safer and wider
access to molecular class 7 was of interest to expand the repertoire
of useful arsine ligands beyond the standard triaryl species.
Based on Blicke's results (Scheme 1b) [10a], we proposed that
di-Grignard reagents 6 would be ideal nucleophiles to react with
oxides 1, given that the second (and evidently most challenging)
AseC bond forming event could occur in an intramolecular mode
(Scheme 2b). An additional advantage offered by this approach over
stepwise processes was the ability to form the desired heterocycles
in a single-pot, avoiding the isolation and purification of organo-
arsine intermediates.
-78-rt
-78-reflux 10
-78-rtc
-78-rt
-78-rt
-78-rt
0-rt
10
10
10
11
11
12
13
14
36
a
Isolated yield based on electrophile.
Et2O used as solvent.
b
c
Reaction time was 70 h.
d
Yield determined by 1H NMR with DMSO as internal standard.
(entry 8), while heating the reaction at reflux was detrimental
(entry 9), possibly due to polymerization of the arsine oxide [12b].
An extension of the reaction time to 70 h did not result in an
improvement (entry 10), establishing that the low yields were not
merely a result of a slow Grignard addition.
Results and discussion
Comparison of previous literature yields using PhAsCl2 reveals a
significant advantage from employing an excess of the di-Grignard
reagent (entries 3 and 6) [17]. This also proved to be the case in our
experiments when the equivalents of 8, relative to (PhAsO)x, were
increased 3- and 5-fold (entries 11 and 12). From the latter reaction
(entry 12), 10 was isolated in an acceptable 42% yield. Translation to
the six-membered homologue with an excess of di-Grignard re-
agent 9 occurred smoothly when the addition was performed at
0 ꢁC, allowing 11 to be obtained in a similar yield (36%, entry 14).
Although it is evident that the previously optimized yields of 10
and 11 from the dichloride electrophile are higher than obtained
here with (PhAsO)x (entry 3 versus 12; entry 6 versus 14), we
believe that the benefits of avoiding hazardous PhAsCl2 outweighs
these current discrepancies. Importantly, the current reactions are
also amenable to larger-scale preparations. The arsine oxide can be
weighed in the air with no special precautions. As an example, we
have prepared 0.8 g of 10 from the reaction between 1.5 g of 3 and
the di-Grignard reagent 8 (42% yield, entry 12).
With phenylarsine oxide established as a viable synthon to cy-
clic arsines, we explored the synthesis of additional heterocycles
using fused di-Grignard reagents (Table 2). Phenyl- and naphthyl-
fused bis-nucleophiles performed adequately in the cyclization,
giving five-membered arsacycles 12 and 13 in 44% and 41% yields
respectively (entries 1 and 2). These results compare well with that
obtained for the non-aromatic analogue 10 (Table 1, entry 12). The
standard flash chromatographic purification with hexanes was
carried out to isolate the analogous six-membered arsine (deoxo)-
14, (entry 3), however the product was found to be contaminated
with non-volatile hydrocarbons derived from Grignard hydrolysis
and Wurtz-coupling processes. Thus, subsequent treatment with
H2O2 [15] was performed to isolate the more polar oxide derivative
14 in an overall 26% yield. It should be noted that desymmetrized
The commercially available phenylarsine oxide 3 was selected as
a model electrophile to begin our investigations. Although 3 is an
oligomeric material, it dissolves readily in standard organic sol-
vents (x ¼ 4 in benzene, CCl4 and camphor) [12a]. Arsenous chlo-
rides have been used as electrophiles in previous syntheses of cyclic
arsines from di-Grignard reagents (Scheme 2a) [14], therefore, by
selecting known arsacycles 10 and 11 as initial targets for reaction
optimization, a direct comparison could be made between the
performance of (PhAsO)x and its corresponding dichloride (Table 1).
Previous results from the literature using PhAsCl2 are therefore
included (entries 1e6) [15e19].
Our opening experiment was performed using an equimolar
quantity of di-Grignard reagent 8 with a 20 h reaction time (entry
7). Following aqueous work-up, the desired arsolane 10 was iso-
lated in 12% yield after elution through silica gel with hexanes. The
remaining material consisted of a complex mixture of unidentified
polar components. Encouraged by our immediate success in the
formation of 10, we proceeded to examine the effect of temperature
variations: mixing the reactants at ꢀ78 ꢁC gave a similar yield
Scheme 2. Proposed synthesis of cyclic arsines from arylarsine oxides and di-Grignard
reagents.

A.M. Gregson et al. / Journal of Organometallic Chemistry 785 (2015) 77e83
79
Table 2
Synthesis of arsine heterocycles 12e16 from carbocyclic-fused di-Grignard reagents.
Entry
1
Di-Grignard precursora
Product
Yield (%)b
44
(12)c
(13)c
Scheme 3. Preparation of novel arsolanes 17e19 from various arylarsine oxides.
2
41
was treated with 3 under the standard conditions of heterocycle
formation. NMR spectroscopic analysis of the resultant mixture
showed no reaction had occurred. This result clearly shows that the
general requirement for excess Grignard reagent is not a conse-
quence of a competing reaction between the formed heterocycle
and the remaining (ArAsO)x. Given that we have also shown that
longer reaction times do not increase the yield of the di-Grignard
cyclization (Table 1, entry 10), we currently speculate that a
higher concentration of the Grignard reagent activates the elec-
trophile by Lewis acid coordination and/or affects the degree of
(ArAsO)x association in solution. Further studies are required to
validate these arguments.
3
4
(14)c
(15)c
26d,e
36
5
(16)
41
(dr ¼ 1:1)
(1)
In the course of this work, we found all arylarsine(III) hetero-
cycles to be relatively stable compounds; no oxidation or decom-
position was observed during work-up and chromatographic
purification, without special precautions to exclude atmospheric
oxygen and moisture. Selected compounds were nonetheless
readily converted to their As(V) analogues by oxidation with H2O2
[15] (Scheme 4). No AseC(sp3) bond cleavage was detected in these
reactions, as has been observed for some acyclic arsines [12c].
a
See the experimental section for Grignard formation conditions.
Isolated yield based on 3.
Racemic mixture.
Reaction performed from 0 ꢁC-rt.
b
c
d
e
Overall isolated yield after oxidation with H2O2.
heterocycles 12e14 have been obtained as racemic mixtures due to
the newly installed arsenic stereocenter. Additionally, both trans-
and cis-cyclohexene-fused di-Grignard reagents reacted produc-
tively under the standard conditions (entries 4 and 5). The racemic
trans product 15, which exhibits solely backbone chirality, was
isolated in 36% yield, while its cis isomer 16, bearing an additional
stereocenter at arsenic, was obtained after silica gel chromatog-
raphy in 41% yield as a 1:1 mixture of the two meso compounds.
Although the yields obtained for known compounds 12 and
(deoxo)-14 are modest (Table 2, entries 1 and 3), they are both
superior to the previous three-step procedures (25% and 17% yields
respectively) [20,21], which involve FriedeleCrafts cyclization and
again use hazardous PhAsCl2 as starting material. Furthermore, we
have fully characterized these compounds for the first time.
Importantly, this metholodogy can also be applied to arylarsine
oxides of electronic and steric variability (Scheme 3). Utilizing di-
Grignard reagent 8 under the established conditions, novel arso-
lanes 17e19, bearing 4-bromophenyl, 4-methoxyphenyl and 1-
naphthyl substituents, were readily obtained in comparable yields
(34ꢀ45%) to their phenyl analogue. The marginally lower yield of
18 was presumably a result of the electron-donating methoxy
group, decreasing the reactivity of the electrophile.
Conclusion
In conclusion, we have demonstrated that arylarsine oxides can
be utilized as synthetic equivalents to their dichloride counterparts
in combination with di-Grignard reagents, allowing the prepara-
tion of cyclic tertiary organoarsines in a significantly less hazardous
manner than previously possible. Extension to carbocyclic-fused di-
Grignard reagents has enabled access to several novel arsacycles,
including those with backbone and arsenic chirality, maintaining
acceptable yields throughout. Modular electronic and steric alter-
ation of the peripheral aryl substituent has also been shown to be
possible. Conveniently, these arylarsine heterocycles are stable to
As a first step to understanding why excess Grignard reagent is
required for satisfactory double AseC bond formation, we carried
out a control experiment to determine whether the cyclic arsine(III)
products were sufficiently nucleophilic to react in situ with their
oxide precursors (Eq (1)) [22]. Accordingly, exemplary substrate 11
a
Scheme 4. Oxidation of selected cyclic arsines. Previously reported in 96% yield but
was not fully characterized [15].

80
A.M. Gregson et al. / Journal of Organometallic Chemistry 785 (2015) 77e83
air and moisture, but can be readily oxidized to their As(V) ana-
logues, which offer potential opportunities for functionalization via
data, with the exception that the quaternary aromatic carbon
[AseC(sp2)] was significantly further downfield than previously
a-lithiation chemistry [23], including oxidative dimerization [24] to
reported (lit:
d
¼ 132.5 [17], our sample:
d
¼ 143.3). 1H NMR (CDCl3,
novel bisarsines. Further studies in our laboratory will include the
examination of solvent effects and/or Lewis acid additives on the
cyclization efficiency, the resolution of chiral racemates 12e15 and
potential applications of the cyclic arsines and derived dimers in
transition metal catalysis.
500 MHz): d 1.76e1.98 (m, 8H), 7.22e7.30 (m, 3H), 7.40e7.44 (m,
2H); 13C NMR (CDCl3, 125 MHz):
143.3.
d 27.4, 30.4, 127.3, 128.3, 131.5,
Synthesis of 1-phenylarsinane (11)
Experimental
A suspension of 1,5-dibromopentane (684 mg, 2.97 mmol) and
Mg (145 mg, 5.97 mmol) in THF (6.3 mL) was stirred at rt for 1.5 h.
The mixture, containing a small amount of unreacted Mg, was
cooled to 0 ꢁC and a solution of (PhAsO)x (100 mg, 0.595 mmol) in
THF (4.2 mL) was added dropwise. The mixture was allowed to
warm to rt and stirred for 20 h. The reaction was quenched with
water (10 mL) and the product extracted with EtOAc (20 mL). The
combined organic layers were washed with brine (20 mL), dried
(MgSO4), concentrated, and subjected to column chromatography
(hexanes) affording 11 [17] (48 mg, 36%) as a colorless oil. This
compound has been fully characterized previously [17]. NMR data
for the sample prepared herein was consistent with the published
data, with the exception that the quaternary aromatic carbon
[AseC(sp2)] was significantly further downfield than previously
General information
All reactions were carried out under an atmosphere of N2 in
oven-dried glassware with magnetic stirring. Thin layer chroma-
tography (TLC) was performed on aluminium-backed 0.20 mm
silica gel plates. Visualization was accomplished with UV light or an
aqueous ceric ammonium molybdate solution. Flash chromatog-
raphy was performed under positive air pressure using Silica Gel 60
of 230e400 mesh (40e63 mm). Infrared (IR) spectra were obtained
with neat samples on a Shimadzu IRAffinity-1 FTIR Spectrometer.
Proton and carbon magnetic resonance spectra (1H NMR and 13C
NMR) were recorded on a Varian Mercury 300 MHz spectrometer, a
Varian Inova 500 MHz spectrometer or a Varian VNMRS PS54
500 MHz spectrometer. All spectra were acquired in CDCl3 and are
reported (lit:
the sample prepared herein was also confirmed by high resolution
mass spectrometry. 1H NMR (CDCl3, 500 MHz):
1.34e1.96 (m,
10H), 7.21e7.44 (m, 5H); 13C NMR (CDCl3, 125 MHz):
d 22.7, 24.4,
d
¼ 132.5 [17], our sample:
d
¼ 141.8). The identity of
reported relative to tetramethylsilane (1H:
d
¼ 0.00 ppm) and sol-
d
vent resonance (13C:
d
¼ 77.0 ppm). 1H NMR data are reported as
follows: chemical shift, multiplicity (d ¼ doublet, t ¼ triplet,
m ¼ multiplet), coupling constant (Hz), integration and assign-
ment. Low resolution mass spectrometry (MS) was performed on a
Shimadzu LC-2010 Electrospray Ionization (ES) Mass Spectrometer
or on a Shimadzu QP-5050 Electron Impact (EI) Spectrometer. High
resolution mass spectrometry (HRMS) was performed on a Waters
Quadrupole-Time of Flight (QTOF) Xevo ES Spectrometer with
Leucine-Enkephalin as an internal standard or on a Fison/VG
Autospec-TOF EI Spectrometer at 70 eV with a source temperature
of 250 ꢁC.
Nitrogen (N2) was dried by passage through self-indicating silica
gel (blue, 2ꢀ4 mm bead size). Known halogenated Grignard pre-
cursors unavailable commercially were prepared according to
literature methods cited within. Grignard reagents were prepared
from Mg turnings that were freshly washed with 1 M HCl, followed
sequentially by water, EtOH, THF and Et2O before being dried under
high vacuum. Phenylarsine oxide (PhAsO)x and anhydrous tetra-
hydrofuran were purchased and used as received. The known 4-
bromo- [25], 4-methoxy-[10b] and 1-napthylarsine oxides [10b]
were prepared in two steps from the corresponding anilines via
diazonium salt activation in the presence of arsenic trioxide [26],
then reduction of the arsonic acids with an iodine/ascorbic acid
system [12d]. All other reagents and solvents were purchased re-
agent grade and used without further purification.
29.0, 127.5, 128.7, 132.0, 141.8; MS (EIþ): 222 (90%) [M]þ, 152 (100%)
[Mꢀ(CH2)5]þ; HRMS (ESþ): calcd for C11H16As 223.0463, found
223.0459.
Synthesis of 1-phenyl-2,3-dihydro-1H-arsindole (12)
A suspension of 1-bromo-2-(2-chloroethyl)benzene [27] (5.00 g,
22.78 mmol) and Mg (1.108 g, 45.56 mmol) in THF (50 mL) was
heated at reflux for 2 h. After cooling to rt, the resulting solution
was added dropwise to a solution of (PhAsO)x (766 mg, 4.56 mmol)
in THF (50 mL) at ꢀ78 ꢁC and the mixture was allowed to warm to rt
and stirred for 20 h. Water (50 mL) was slowly added and the
mixture was extracted with Et2O (3 ꢂ 50 mL). The combined
organic extracts were dried (MgSO4), concentrated and subjected to
column chromatography (hexanes) giving 12 [20] (523 mg, 44%) as
a colorless oil. This compound has not been fully characterized
previously. FTIR: v 3384, 3046, 2360, 1435, 872, 765, 733, 696 cmꢀ1
;
1H NMR (CDCl3, 300 MHz):
d 2.08e2.26 (m, 2H), 3.15e3.35 (m, 2H),
7.19e7.21 (m, 5H), 7.20e7.36 (m, 3H), 7.65 (d, J ¼ 6.6 Hz, 1H); 13C
NMR (CDCl3, 75 MHz):
d 26.7, 36.4, 125.0, 126.5, 127.7, 128.3, 128.6,
131.8, 131.9, 140.9, 142.7, 150.8; MS (EIþ): 256 (77%) [M]þ, 227
(40%), 179 (100%); HRMS (ESþ): calcd for C14H14As 257.0311, found
257.0321.
Synthesis of 1-bromo-2-(2-chloroethyl)naphthalene (novel
Synthesis of 1-phenylarsolane (10)
precursor to 13)
A
suspension of Mg (2.215 g, 91.12 mmol) and 1,4-
A mixture of 2-(1-bromonaphthalen-2-yl)ethanol [28] (25.00 g,
99.55 mmol) and PCl5 (31.10 g, 149.33 mmol) in CHCl3 (200 mL) was
heated at reflux for 4 h. Upon cooling to rt, water (100 mL) was
added dropwise and the mixture was diluted with CH2Cl2 (200 mL).
The organic layer was separated and the aqueous layer was
extracted with CH2Cl2 (2 ꢂ 150 mL). The combined organic layers
were dried (MgSO4) then concentrated in vacuo and the residue
subjected to silica gel chromatography. Elution with hexanes gave
1-bromo-2-(2-chloroethyl)naphthalene (25.50 g, 95%) as a pale
yellow solid. mp: 42e43 ꢁC; FTIR: v 1321, 1259, 967, 817, 759,
dibromobutane (9.838 g, 45.56 mmol) in THF (70 mL) was stirred
at rt for 1 h. The resulting dark grey solution was added dropwise to
a solution of (PhAsO)x (1.532 g, 9.11 mmol) in THF (70 mL) at ꢀ78 ꢁC
and the mixture was allowed to warm to rt and stirred for 20 h.
Water (50 mL) was slowly added and the mixture was extracted
with CH2Cl2 (3 ꢂ 50 mL). The combined extracts were dried
(MgSO4), concentrated and subjected to column chromatography
(hexanes) giving 10 [17] (803 mg, 42%) as a colorless oil. This
compound has been fully characterized previously [17]. NMR data
for the sample prepared herein was consistent with the published
706 cmꢀ1; 1H NMR (CDCl3, 500 MHz):
d
3.44 (t, J ¼ 7.5 Hz, 2H), 3.82

A.M. Gregson et al. / Journal of Organometallic Chemistry 785 (2015) 77e83
81
(t, J ¼ 7.5 Hz, 2H), 7.37 (d, J ¼ 8.5 Hz, 1H), 7.50 (t, J ¼ 8.0 Hz, 1H), 7.58
(t, J ¼ 7.5 Hz, 1H), 7.76 (d, J ¼ 8.0 Hz, 1H), 7.80 (d, J ¼ 8.0 Hz,1H), 8.31
added. The resulting solution was then heated between 40 and
50 ꢁC for 48 h. Water (50 mL) was added and the mixture was
extracted with EtOAc (3 ꢂ 50 mL). The combined extracts were
dried (MgSO4), concentrated and subjected to column chromatog-
raphy (hexanes) giving (rac)-trans-4,5-bis(bromomethyl)cyclohex-
1-ene (15.05 g, 60% over two steps) as a yellow oil. FTIR: v 3027,
2898, 1430, 1276, 1223, 1034, 978, 924, 850, 768, 668, 607 cmꢀ1; 1H
(d, J ¼ 8.5 Hz, 1H); 13C NMR (CDCl3, 125 MHz):
d 40.7, 43.3, 124.5,
126.5, 127.5, 127.7, 127.9, 128.2, 128.6, 132.7, 133.8, 135.7; MS (EIþ):
270 (99%) [M, 81Br/35Cl]þ, 268 (100%) [M, 79Br/35Cl]þ; HRMS (EIþ):
calcd for C12H1079Br35Cl 267.9654, found 267.9657.
Synthesis of 1-phenyl-2,3-dihydro-1H-benzo[g]arsindole (13)
NMR (CDCl3, 300 MHz):
d
1.98e2.25 (m, 6H), 3.45e3.53 (m, 2H),
28.4,
3.60e3.67 (m, 2H), 5.64 (s, 2H); 13C NMR (CDCl3, 75 MHz):
d
A suspension of Mg (1.45 g, 59.5 mmol) and 1-bromo-2-(2-
chloroethyl)naphthalene (8.02 g, 29.76 mmol) in THF (70 mL) was
heated at reflux for 12 h. After cooling to rt, the dark grey/brown
solution was added dropwise to a solution of (PhAsO)x (1.00 g,
5.95 mmol) in THF (70 mL) at ꢀ78 ꢁC and the mixture was allowed
to warm to rt and stirred for 20 h. Water (50 mL) was slowly added
and the mixture was extracted with Et2O (3 ꢂ 50 mL). The com-
bined extracts were dried (MgSO4), concentrated and subjected to
column chromatography (hexanes) giving 13 (746 mg, 41%) as a
colorless oil. FTIR: v 3047, 2961, 2916, 2849, 1432, 1023, 810, 773,
36.2, 37.8, 125.0; MS (EIþ): 270 (3%) [M, 81Br]þ, 268 (6%) [M,
81Br/79Br]þ, 266 (3%) [M, 79Br]þ, 189 (45%) [MꢀBr, 81Br]þ, 187 (49%)
[MꢀBr, 79Br]þ, 107 (100%).
Synthesis of (rac)-trans-2-phenyl-2,3,3a,4,7,7a-hexahydro-1H-
isoarsindole (15)
A suspension of Mg (0.363 g, 14.93 mmol) and (rac)-trans-4,5-
bis(bromomethyl)cyclohex-1-ene (1.000 g, 3.73 mmol) in THF
(4 mL) was stirred at rt for 1 h. The supernatant liquid was added
dropwise to a solution of (PhAsO)x (0.125 g, 0.74 mmol) in THF
(4 mL) at ꢀ78 ꢁC and the mixture was allowed to warm to rt and
stirred for 20 h. Water (5 mL) was slowly added and the mixture
was extracted with CH2Cl2 (3 ꢂ 10 mL). The combined extracts were
dried (MgSO4), concentrated and subjected to column chromatog-
raphy (hexanes) giving 15 (69 mg, 36%) as a colorless oil. FTIR: v
734, 693 cmꢀ1 1H NMR (CDCl3, 500 MHz):
; d 2.21e2.27 (m, 1H),
2.32e2.38 (m, 1H), 3.48e3.51 (m, 2H), 7.14e7.19 (m, 5H), 7.41e7.49
(m, 3H), 7.81e7.86 (m, 2H), 7.93e7.94 (m, 1H); 13C NMR (CDCl3,
125 MHz): 26.1, 37.9, 123.6, 125.2, 126.7, 127.9, 128.27, 128.33, 128.7,
129.4, 132.1, 132.4, 135.3, 140.6, 140.7, 149.5; MS (ESþ): 307 (30%)
[MþH]þ, 323 (100%) [M þ NH4]þ; HRMS (ESþ): calcd for C18H16As
307.0468, found 307.0481.
3858, 3019, 2900, 1701, 1559, 1507, 1043, 774, 731, 694, 655 cmꢀ1
1H NMR (CDCl3, 500 MHz):
1.39e1.68 (m, 4H), 1.79e1.94 (m, 2H),
2.22e2.45 (m, 3H), 2.50e2.57 (m, 1H), 5.61 (s, 2H),7.21e7.32 (m,
3H), 7.42e7.48 (m, 2H); 13C NMR (CDCl3, 125 MHz):
33.9, 34.4,
;
d
Synthesis of 1-phenyl-1,2,3,4-tetrahydroarsinoline-1-oxide (14)
d
A suspension of Mg (785 mg, 32.31 mmol) and 1-bromo-2-(3-
bromopropyl)benzene [29] (4.49 g, 16.15 mmol) in THF (10 mL)
was stirred at rt for 12 h. The mixture was cooled to 0 ꢁC and a
solution of (PhAsO)x (679 mg, 4.04 mmol) in THF (10 mL) was added
dropwise. The mixture was allowed to warm to rt and stirred for
20 h. The reaction was quenched with water (10 mL) and the
product extracted with CH2Cl2 (20 mL). The combined organic
layers were washed with brine (10 mL), dried (MgSO4), concen-
trated and subjected to column chromatography (petroleum ether)
giving a mixture of 1-phenyl-1,2,3,4-tetrahydroarsinoline (deoxo-
14) and a Wurtz coupling-derived Grignard hydrolysis side prod-
uct: 1,6-diphenylhexane (387 mg total). The mixture was taken up
in acetone (10 mL) and H2O2 (30% aqueous, 167 mg total, 1.43 mmol
H2O2) was added and the solution was stirred at rt for 12 h. The
solution was concentrated under reduced pressure and the residual
solid was triturated with hexanes to provide 14 (340 mg, 26%) as a
white foam. FTIR: v 3363, 2930, 1697, 1438, 1269, 1262, 1087, 1066,
996, 874, 852, 802, 773, 743, 716 cmꢀ1; 1H NMR (CDCl3, 500 MHz):
35.2, 35.3, 43.3, 44.0, 126.6, 126.7, 127.4, 128.4, 131.6, 143.5; MS
(ESþ): 261 (100%) [MþH]þ; HRMS (ESþ): calcd for C14H18As
261.0624, found 261.0634.
Synthesis of (meso)-(2r,3aR,7aS)-2-phenyl-2,3,3a,4,7,7a-
hexahydro-1H-isoarsindole (16r) and (meso)-(2s,3aR,7aS)-2-
phenyl-2,3,3a,4,7,7a-hexahydro-1H-isoarsindole (16s)
A suspension of Mg (0.308 g, 12.67 mmol) and (meso)-(4R,5S)-
4,5-bis(bromomethyl)cyclohex-1-ene [31] (0.850 g, 3.17 mmol) in
THF (3.4 mL) was stirred at rt for 1 h. The supernatant liquid was
added dropwise to a solution of (PhAsO)x (0.107 g, 0.64 mmol) in
THF (3.4 mL) at ꢀ78 ꢁC and the mixture was allowed to warm to rt
and stirred for 20 h. Water (5 mL) was slowly added and the
mixture was extracted with CH2Cl2 (3 ꢂ 10 mL). The combined
extracts were dried (MgSO4), concentrated and subjected to col-
umn chromatography (hexanes) giving an inseparable mixture of
meso-diastereomers 16s and 16r (67 mg, dr ¼ 1:1, 41% combined
yield) as a colorless oil. FTIR: v 3741, 2915, 1653, 1540, 1038, 880,
d
2.20e2.28 (m, 1H), 2.30e2.40 (m, 1H), 2.52e2.60 (m, 1H),
2.70e2.78 (m, 1H), 2.88e2.96 (m, 1H), 3.04e3.12 (m, 1H), 7.24e7.72
(m, 9H); 13C NMR (CDCl3, 125 MHz):
22.1, 30.9, 32.2, 128.1, 129.3,
732, 657 cmꢀ1; 1H NMR (CDCl3, 500 MHz, as mixture):
(m, 20H), 5.48 (s, 2H), 5.62 (s, 2H), 7.17e7.50 (m, 10H); 13C NMR
(CDCl3,125 MHz, as mixture): 27.9, 28.7, 31.1, 31.8, 39.6, 39.7,124.7,
d 1.65e2.40
d
129.5, 130.0, 130.7, 132.2, 132.3, 132.5, 134.5, 145.2; MS (ESþ): 287
d
(95%) [MþH]þ, 572 (100%) [2M þ H]þ; HRMS (ESþ): calcd for
125.2, 126.8, 127.4, 128.3, 128.4, 130.5, 131.7, 143.4, 145.6; MS (ESþ):
261 (100%) [MþH]þ; HRMS (ESþ): calcd for C14H18As 261.0624,
found 261.0616.
C
15H16AsO 287.0417, found 287.0405.
Synthesis of (rac)-trans-4,5-bis(bromomethyl)cyclohex-1-ene (novel
precursor to 15)
Synthesis of 1-(4-bromophenyl)arsolane (17)
To a solution of (rac)-trans-4,5-bis(hydroxymethyl)cyclohex-1-
ene [30] (13.25 g, 93.17 mmol) in CH2Cl2 (50 mL) at 0 ꢁC was
added sequentially NEt3 (32.3 mL, 232.91 mmol) and MsCl (15.9 mL,
204.97 mmol) and the resulting suspension was allowed to warm to
rt and stirred for 3 h. Water (50 mL) was slowly added and the
mixture was extracted with EtOAc (3 ꢂ 50 mL). The combined ex-
tracts were dried (MgSO4) and concentrated. The crude dimesylate
was taken up in THF (100 mL) and LiBr (37.00 g, 426.05 mmol) was
A suspension of Mg (470 mg, 19.33 mmol) and 1,4-
dibromobutane (1.386 g, 6.42 mmol) in THF (12.8 mL) was stirred
at rt for 16 h. The supernatant liquid was added dropwise to a so-
lution of (4-BrPhAsO)x (406.7 mg, 1.65 mmol) in THF (16.5 mL)
at ꢀ78 ꢁC and the mixture was allowed to warm to rt and stirred for
20 h. The reaction was quenched by the slow addition of saturated
NH4Cl (10 mL), then water (20 mL) was added and the product was
extracted with Et2O (2 ꢂ 20 mL). The combined organic extracts

82
A.M. Gregson et al. / Journal of Organometallic Chemistry 785 (2015) 77e83
were washed with brine (20 mL), dried (Na2SO4), concentrated and
subjected to column chromatography (petroleum ether) giving 17
(211.5 mg, 45%) as a colorless oil. FTIR: v 3331, 2917, 1653, 1479,
Synthesis of 1-phenylarsinane-1-oxide (21)
To a solution of 11 (220 mg, 0.99 mmol) in acetone (5 mL) was
added H2O2 (30% aqueous, 112 mg total, 0.99 mmol H2O2) and the
solution was stirred at rt for 12 h. The solution was concentrated
under reduced pressure and the residue was subjected to column
chromatography (10:20:70 MeOH:NEt3:EtOAc to 20:20:60
MeOH:NEt3:EtOAc) to give 21 (210 mg, 91%) as a yellow oil. FTIR: v
3335, 2922, 2853, 1434, 1089, 1021, 930, 887, 863, 809, 747,
1377, 1043, 1007, 799, 704 cmꢀ1 1H NMR (CDCl3, 300 MHz):
;
d
1.72e2.04 (m, 8H), 7.28 (d, J ¼ 8.2 Hz, 2H), 7.41 (d, J ¼ 8.2 Hz, 2H);
13C NMR (CDCl3, 75 MHz):
d
27.5, 30.4, 121.6, 131.2, 133.1, 142.2; MS
(EIþ): 288 (11%) [M, 81Br]þ, 286 (11%) [M, 79Br]þ, 232 (15%), 230
(19%), 71 (100%); HRMS (EIþ): calcd for C10H12As79Br 285.9338,
found 285.9349.
740 cmꢀ1
; d 1.58e2.42 (m, 10H),
1H NMR (CDCl3, 500 MHz):
7.50e7.58 (m, 3H), 7.76e7.82 (m, 2H); 13C NMR (CDCl3, 125 MHz):
Synthesis of 1-(4-methoxyphenyl)arsolane (18)
d
23.3, 25.4, 29.5, 129.2, 129.9, 131.8, 133.6; MS (ESþ): 239 (40%)
[MþH]þ, 477 (100%) [2M þ H]þ; HRMS (ESþ): calcd for C11H16AsO,
A
suspension of Mg (245 mg, 10.10 mmol) and 1,4-
239.0417 found 239.0420.
dibromobutane (1.090 g, 5.05 mmol) in THF (5 mL) was stirred at
rt for 1 h. The resulting dark grey solution was added dropwise to a
solution of (4-OMePhAsO)x (200 mg, 1.01 mmol) in THF (9 mL)
at ꢀ78 ꢁC and the mixture was allowed to warm to rt and stirred for
20 h. Water (5 mL) was slowly added and the mixture was extracted
with EtOAc (2 ꢂ 10 mL). The combined extracts were washed with
brine (10 mL), dried (MgSO4), concentrated and subjected to col-
umn chromatography (hexanes) giving 18 (81.4 mg, 34%) as a
colorless oil. FTIR: v 3320, 2925, 2317, 1700, 1653, 1507, 1044,
Synthesis of 1-phenyl-2,3-dihydro-1H-arsindole-1-oxide (22)
To a solution of 12 (500 mg, 1.92 mmol) in acetone (10 mL) was
added H2O2 (30% aqueous, 327 mg total, 2.88 mmol H2O2) and the
solution was stirred at rt for 12 h. The solution was concentrated
under reduced pressure and the residue subjected to column
chromatography (EtOAc to 20% NEt3/EtOAc) to give 22 (468 mg,
89%) as a colorless oil. FTIR: v 3323, 3056,1653,1437,1086, 866, 740,
668 cmꢀ1; 1H NMR (CDCl3, 500 MHz):
d 1.73e1.95 (m, 8H), 3.77 (s,
691 cmꢀ1 1H NMR (CDCl3, 500 MHz):
; d 2.50e2.62 (m, 2H),
3H), 6.85 (d, J ¼ 8.3 Hz, 2H), 7.34 (d, J ¼ 8.3 Hz, 2H); 13C NMR (CDCl3,
3.36e3.42 (m, 1H), 3.55e3.61 (m, 1H), 7.39e7.57 (m, 5H), 7.65 (d,
J ¼ 7.5 Hz, 2H), 7.71 (d, J ¼ 7.5 Hz, 1H); 13C NMR (CDCl3, 125 MHz):
27.5, 29.7, 127.2, 128.5, 129.4, 129.8, 130.3, 132.1, 132.6, 132.7, 134.4,
146.3; MS (ESþ): 273 (100%) [MþH]þ; HRMS (ESþ): calcd for
125 MHz):
d
27.7, 30.5, 55.2,114.1, 132.9, 133.6, 159.4; MS (ESþ): 239
(100%) [MþH]þ; HRMS (ESþ): calcd for C11H16AsO 239.0417, found
239.0424.
C14H14OAs 273.0261, found 273.0251.
Synthesis of 1-(naphthalen-1-yl)arsolane (19)
Synthesis of 1-phenyl-2,3-dihydro-1H-benzo[g]arsindole-1-oxide
(23)
A
suspension of Mg (223 mg, 9.17 mmol) and 1,4-
dibromobutane (990 mg, 4.59 mmol) in THF (5 mL) was stirred at
rt for 1 h. The resulting dark grey solution was added dropwise to a
solution of (1-naphthylAsO)x (200 mg, 0.92 mmol) in THF (9 mL)
at ꢀ78 ꢁC and the mixture was allowed to warm to rt and stirred for
20 h. Water (20 mL) was slowly added and the mixture was
extracted with EtOAc (2 ꢂ 20 mL). The combined extracts were
washed with brine (20 mL), dried (MgSO4), concentrated and
subjected to column chromatography (hexanes) giving 19 (87.6 mg,
37%) as a colorless oil. FTIR: v 3741, 2927, 1701, 1255, 1022, 947, 787,
To a solution of 13 (400 mg, 1.31 mmol) in acetone (10 mL) was
added H2O2 (30% aqueous, 222 mg total, 1.96 mmol H2O2) and the
solution was stirred at rt for 12 h. The solution was concentrated
under reduced pressure and the residual solid was triturated with
cold CH2Cl2 providing 23 (394 mg, 94%) as a whiteꢀ1solid. mp:
106e107 ꢁC; FTIR: v 3104, 2830, 845, 811, 744, 692 cm
;
1H NMR
(CDCl3, 500 MHz):
d 2.62e2.68 (m, 1H), 2.76e2.82 (m, 1H),
3.53e3.59 (m, 1H), 3.71e3.77 (m, 1H), 7.46e7.51 (m, 6H), 7.70 (d,
J ¼ 7.5 Hz, 2H), 7.90 (d, J ¼ 7.5 Hz,1H), 7.98 (d, J ¼ 7.5 Hz,1H), 8.03 (d,
770, 649 cmꢀ1 1H NMR (CDCl3, 500 MHz):
; d 1.73e1.86 (m, 4H),
J ¼ 8.5 Hz, 1H); 13C NMR (CDCl3, 125 MHz):
d 27.1, 30.2, 124.3, 126.0,
126.6, 128.1, 128.3, 128.7, 129.3, 129.9, 132.0, 132.1, 133.0, 133.5,
1.97e2.09 (m, 4H), 7.36 (t, J ¼ 7.6 Hz, 1H), 7.41e7.55 (m, 3H), 7.72 (d,
J ¼ 8.1 Hz, 1H), 7.80 (d, J ¼ 7.6 Hz, 1H), 8.30 (d, J ¼ 8.2 Hz, 1H); 13
C
134.5, 146.4; MS (ESþ): 323 (100%) [MþH]þ; HRMS (ESþ): calcd for
NMR (CDCl3, 125 MHz):
d 26.3, 30.3, 125.2, 125.55, 125.57, 126.7,
C18H16AsO 323.0417, found 323.0425.
127.2, 127.9, 128.8, 133.9, 135.4, 140.5; MS (ESþ): 259 (100%)
[MþH]þ; HRMS (ESþ): calcd for C14H16As 259.0468, found
259.0468.
Synthesis of 1-(4-methoxyphenyl)arsolane-1-oxide (24)
To a solution of 18 (39.8 mg, 0.17 mmol) in acetone (1.2 mL) was
added H2O2 (30% aqueous, 19.2 mg total, 0.17 mmol H2O2) and the
solution was stirred at rt for 30 min. The solution was concentrated
under reduced pressure and the residue subjected to column
chromatography (CH2Cl2 to 10% MeOH/CH2Cl2) to give 24 (33 mg,
79%) as a colorless oil. FTIR: v 3353, 2941, 1507, 1090, 1019, 884, 868,
Synthesis of 1-phenylarsolane-1-oxide (20)
Based on a literature procedure [15], to a solution of 10 (700 mg,
3.36 mmol) in acetone (10 mL) was added H2O2 (30% aqueous,
573 mg total, 5.05 mmol H2O2) and the solution was stirred at rt for
12 h. The solution was concentrated under reduced pressure and
the residue subjected to column chromatography (EtOAc to 20%
NEt3/EtOAc) to afford 20 [15] (678 mg, 90%) as a colorless oil. This
compound has not been fully characterized previously. FTIR: v 3321,
821, 794, 752, 608 cmꢀ1
; d 1.96e2.25
1H NMR (CDCl3, 500 MHz):
(m, 8H), 3.86 (s, 3H), 7.04 (d, J ¼ 8.5 Hz, 2H), 7.65 (d, J ¼ 8.5 Hz, 2H);
13C NMR (CDCl3, 125 MHz):
d 25.9, 29.3, 55.4, 114.9, 125.3, 131.2,
162.4; MS (ESþ): 255 (100%) [MþH]þ; HRMS (ESþ): calcd for
2971, 2874, 1439, 1378, 1089, 1048, 879, 863, 740, 692 cmꢀ1
;
1H
C11H16AsO2 255.0366, found 255.0360.
NMR (CDCl3, 500 MHz): 1.97e2.05 (m, 2H), 2.13e2.28 (m, 6H),
d
7.50e7.60 (m, 3H), 7.72e7.78 (m, 2H); 13C NMR (CDCl3, 125 MHz):
d
Acknowledgements
25.9, 29.2, 129.1, 129.5, 131.7, 134.8; MS (EIþ): 224 (25%) [M]þ, 169
(100%); HRMS (ESþ): calcd for
C
10H14OAs 225.0261, found
A.M.G. and S.J.B. thank the University of Wollongong for the
provision of a PhD scholarship.
225.0255.

A.M. Gregson et al. / Journal of Organometallic Chemistry 785 (2015) 77e83
83
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