Cyclic Phosphine Oxides and Phosphinamides from Di-Grignard Reagents and Phosphonic Dichlorides: Modular Access to Annulated Phospholanes

Article abstract of DOI:10.1021/acs.joc.5b01476

The reaction between 1,4-di-Grignard reagents and phosphonous(III) dichlorides is a classical method for the direct synthesis of phospholanes. Reported here is an extension of this approach to the preparation of value-added, annulated phospholane oxides, achieved through the combination of carbocyclic-fused di-Grignard reagents and readily available phosphonic(V) dichlorides. The procedure is amenable to (benz)annulation at both the 2,3- and 3,4-positions of the phospholane ring, and a variety of aliphatic, cyclic and aryl P-electrophiles are tolerated in reasonable to excellent yields.

Full text of DOI:10.1021/acs.joc.5b01476

Note
pubs.acs.org/joc
Cyclic Phosphine Oxides and Phosphinamides from Di-Grignard
Reagents and Phosphonic Dichlorides: Modular Access to Annulated
Phospholanes
Aaron M. Gregson,†,§ Steven M. Wales,†,§ Stephen J. Bailey,†,§ Anthony C. Willis,‡ and Paul A. Keller*,†
†School of Chemistry, University of Wollongong, Wollongong, NSW 2522, Australia
‡Research School of Chemistry, The Australian National University, Canberra, ACT 2601, Australia
S
* Supporting Information
ABSTRACT: The reaction between 1,4-di-Grignard reagents
and phosphonous(III) dichlorides is a classical method for the
direct synthesis of phospholanes. Reported here is an
extension of this approach to the preparation of value-added,
annulated phospholane oxides, achieved through the combi-
nation of carbocyclic-fused di-Grignard reagents and readily
available phosphonic(V) dichlorides. The procedure is
amenable to (benz)annulation at both the 2,3- and 3,4-positions of the phospholane ring, and a variety of aliphatic, cyclic
and aryl P-electrophiles are tolerated in reasonable to excellent yields.
he phospholane ring system is a ubiquitous heterocycle in
organic synthesis, upon which a plethora of P-ligands1 and
Recently, phospholane oxides and their bi- and tricyclic
derivatives (fused and bridged) have emerged as effective
precatalysts for an expanding new area of organocatalysis
involving the P(III): ↔ P(V)O redox pair (e.g., 7−9, Figure
1).7 The virtue of these heterocycles to participate in such a
catalysis mode stems from their increased rate of reduction
compared to that of their larger ring-homologues and acyclic
counterparts.7,8 Current areas of development include catalytic
Wittig,9 aza-Wittig,10 and Appel reactions8,11 and, very recently,
deoxygenative condensations.12
T
nucleophilic organocatalysts1c,2 are based. In particular, the
privileged BPE and DuPhos families,3 bearing 2,5-disubstituted
phospholanes (1 and 2, Figure 1), have seen extensive
The most common approach to assemble the phospholane
system involves the combination of lithiated primary
phosphines or phosphine-boranes with 1,4-bis-electrophiles,
enabling consecutive inter- and intramolecular P−C bond
formations in a single pot. This strategy has furnished a range of
valuable phospholanes,1c including bicyclic adducts,5a,b,13 and
can be extended to secondary alkyl electrophiles in a
stereospecific manner.3a,14 Despite these favorable aspects, the
requirement for the handling and use of pungent, odorous, and
potentially pyrophoric primary phosphines remains a significant
drawback. Furthermore, this approach is not readily amenable
to benzannulation at the phospholane 2,3-position,15 an
emerging structural feature of useful ligands and organocatalysts
(e.g., 6 and 9, Figure 1).8,12a,15,16
In our search for an alternate phospholane syntheses that
would avoid the use of primary phosphines, while still
circumventing acyclic organophosphorus intermediates17 and
backbone redox manipulations,18 common to most available
routes, we turned our attention to the classical umpolung
approach, in which a 1,4-diorganometallic reagent is reacted
Figure 1. Exemplary P-ligands and organocatalysts containing the
phospholane moiety.
application in metal-mediated4 and metal-free asymmetric
catalysis.2 The P-stereogenic TangPhos/DuanPhos/ZhangPhos
series (3−5),5 based on 1,1′-di-tert-butyl-2,2′-biphospholane
and its 3,4-annulated derivatives, is another notable contribu-
tion, encompassing some of the most effective ligands ever
reported for asymmetric hydrogenation.6
Received: July 15, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.joc.5b01476
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Note
with a P-electrophile. This method was first introduced by
we were inspired to investigate in more detail the application of
carbocyclic-fused di-Grignard reagents 12 in this setting.23
From an additional standpoint, we were drawn to the potential
of using higher oxidation level phosphonic(V) dichlorides as
electrophiles, which have, surprisingly, remained an essentially
unexplored class of reagents for phospholane synthesis,24 or
homologues thereof. Notably, the latter modification would
open up a direct entry to phospholane oxides (Scheme 1b).
Several practical benefits of their use also could be envisioned,
including the stability of P(V) reagents to oxygen, the wide
range of commercially available phosphonic dichlorides and
their phosphonic acid precursors,25 and the avoidance of an
oxidative workup otherwise required to isolate the desired P-
oxide.
Gruttner for the preparation of phenyl phospholane from di-
̈
Grignard reagent 10 (Scheme 1a)19 and has since been applied
Scheme 1. Proposed Synthesis of Annulated Phospholanes
Our initial synthetic investigations were based on phenyl
phospholane oxide (19 in Table 1) as a model system through
the reaction of di-Grignard reagent 10 and commercially
available POPhCl2. A previous study of a related reaction
between phosphate ester dichlorides (PO(OR)Cl2) and 10
highlighted the difficulty in achieving cyclization at the P(V)
oxidation state due to undesired oligomerizaton.26 After
experiencing similarly low yields of 19 (25−35%) under
standard conditions (0 °C to rt),19,20,26 we progressed to
examine the effect of lower temperatures, which, surprisingly, to
our knowledge, had never been investigated for the related
esters.26 In the event, by mixing the reactants at −78 °C (1:1 in
to a variety of analogues 11 using phosphonous(III)
dichlorides5c,14b,20 or other trivalent P reagents,21 typically by
trapping the products as their stable borane or sulfide adducts.
Encouraged by these findings, and considering the fact that
extensions of this umpolung synthetic strategy to monoannu-
lated phospholanes (i.e., 13, Scheme 1b) have been limited,22
a
Table 1. Di-Grignard Scope
a
b
Reactions performed with 0.30−0.58 mmol of POPhCl2 at 0.05−0.10 M. Di-Grignard reagents were prepared in THF with 2.1 equiv of acid-
c
d
washed Mg flakes and titrated with 1,10-phenanthroline/2-butanol prior to use. Isolated yield after flash chromatography. Highest yield reported
among all previous methods. Yield of the corresponding BH3 adduct obtained from 10 and PPhCl2. Yield of deoxo-19 obtained from Li(CH2)4Li
and PPh(OMe)2. Diastereomers separated by flash chromatography.
e
f
g
B
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a
THF, 0.1 M), a significant suppression of oligomerization was
realized to give 19 in a highly respectable 75% yield (Table 1,
entry 1), representing a notable improvement relative to
previous syntheses of phenyl phospholane from diorganome-
tallic and P(III) reagents (optimum lit. yields given in Table 1,
entry 1).19,20a,b,27
Table 2. Electrophile Scope
With a practical and efficient procedure established, we
submitted a series of carbocyclic-fused 1,4-di-Grignard reagents
(14−17) to the reaction with POPhCl2 (Table 1, entries 2−5).
The known P-stereogenic benzo- and naphthophospholanes
( )-20 and ( )-21 were obtained in 87 and 57% yields,
respectively, comparing favorably with previous multistep
routes to these compounds (entries 2 and 3).28−30 Utilizing
racemic di-Grignard reagent 16, the novel bicyclic phospholane
oxide ( )-22 was isolated in a moderate 57% yield (entry 4).
The rigid trans-cyclohexane-annulated chiral backbone of 22
represents an unsaturated monomeric analogue to the skeleton
of ZhangPhos (5, Figure 1), which has been previously
obtained by the inverse addition of a nucleophilic primary
phosphine and the corresponding 1,4-bis-electrophile.5a Trans-
lation to the homochiral variants of 22 can be readily
envisioned, based on the commercial availability of the requisite
enantiopure precursors.31
The corresponding cis-di-Grignard reagent 17 reacted
similarly with PPhOCl2 to give chromatographically separable
meso-diastereomers (sP)-23 and (rP)-23 in a 59% combined
yield (Table 1, entry 5), which bear additional P-stereocenters
on the molecular symmetry plane. The major isomer was
determined by X-ray crystallography to have the (sP)-
configuration at the phosphorus atom, in which the phenyl
group lies in an exo relationship to the annulated cyclohexene
ring (Figure 2). We also established that the method can be
a
Reactions performed with 0.32−0.50 mmol of PORCl2 at 0.08−0.10
M. Yields are of isolated product after flash chromatography.
b
Chlorination conditions: (COCl)2, DMF (cat.), CH2Cl2, rt to 40
°C, 1 h.25 PORCl2 was obtained commercially. The ellipsoid contour
probability level of the X-ray structure of 27 is 30%.
c
performed particularly well, giving ( )-27 in 79% yield, the
structure of which was confirmed by X-ray crystallography
(Table 2, inset). Importantly, sterically encumbered aliphatic P-
substituents commonly exploited in phosphine ligands were
well-tolerated, including tert-butyl and cyclohexyl moieties. A
phosphoramide dichloride (PO(NMe2)Cl2) was also accom-
modated, affording phosphinamide derivative ( )-31 in high
yield (88%).
In addition to having showcased the ability to tune the
electronic and steric properties of the naphthophospholane
scaffold via this methodology, it is noteworthy that versatile
functional handles for further manipulation have been
introduced (e.g., allyl, bromo, and methoxy). On the basis of
more specific precedents, the methoxy group could offer a
potential means of resolving ( )-25 via the diastereomeric
menthyl carbonates,16 whereas the phosphinamide moiety in
31 should permit a facile entry into the corresponding
phosphonic acid,35 which could, for instance, be reduced to
the corresponding secondary phosphine oxide35b,36 or the
secondary phosphine3a,36 or could be diastereomerically
resolved.35b
In summary, we have established that annulated phospholane
oxides can be obtained in a practical and efficient manner
through the combination of phosphonic dichlorides and di-
Grignard reagents. The significance of this method has been
demonstrated by the synthesis of representative known
compounds in yields superior to those obtained with previous
methods, its application to backbone-chiral and P-stereogenic
phospholanes, and the straightforward electronic and steric
modulation of a representative heterocycle through P-
substituent variations. The latter is of particular importance in
Figure 2. X-ray crystal structure of meso-(sP)-23 with an ellipsoid
contour probability level of 30%.
extended to six-membered homologues using exemplary di-
Grignard reagent 18 (entry 6); however, reduced yields should
be expected due to a greater degree of oligomerization.33
We next turned our attention to the scope of the process
with respect to the phosphonic dichloride, targeting a series of
novel naphthophospholane derivatives (Table 2). The requisite
electrophiles were obtained commercially or by a simple
chlorination procedure using oxalyl chloride,25,34 allowing
access to a variety of products (25−31) in moderate to
excellent yields (49−88%). Functionalized 2-methoxy- and 3-
bromophenylphosphonic dichlorides provided ( )-25 and
( )-26 in yields comparable to that of their unsubstituted
analogue ( )-21 (Table 1, entry 3). The 1-naphthyl substrate
C
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Note
under reduced pressure. Flash chromatography with the specified
eluent provided the desired cyclic phosphine oxide.
the context of analogue throughput in catalyst screening
studies, which, as pointed out, could involve applications of the
phospholane oxides as new organocatalysts or alternatively, as
templates for P-ligand design, based on their well-precedented
ability to undergo diastereoselective α-C(sp3)−H functionali-
zation,18a,37 including oxidative dimerization to 1,2-bisphosphi-
nes.5b,16
1-Phenylphospholane-1-oxide (19). This was prepared according
to General Procedure B using a solution of POPhCl2 (97.5 mg, 0.50
mmol) in THF (3.31 mL) and a solution of di-Grignard reagent 10
(0.295 M in THF, 1.69 mL, 0.50 mmol). Flash chromatography (100%
EtOAc to 2% NEt3/EtOAc) gave the known phospholane 19 (67.6
mg, 75%) as a yellow oil. NMR data was in good agreement with that
previously reported.8 TLC (2% NEt3/EtOAc) Rf = 0.20; H NMR
1
(500 MHz, CDCl3) δ 7.74 (dd, J = 11.4, 7.3 Hz, 2H), 7.56−7.46 (m,
3H), 2.27−1.88 (m, 8H); 13C NMR (125 MHz, CDCl3) δ 133.9 (d, J
= 90.1 Hz), 131.4 (d, J = 2.9 Hz), 129.6 (d, J = 9.6 Hz), 128.4 (d, J =
11.6 Hz), 29.4 (d, J = 67.6 Hz), 25.0 (d, J = 8.1 Hz).
EXPERIMENTAL SECTION
■
General Methods and Materials. All reactions were carried out
in standard laboratory glassware with magnetic stirring. Thin-layer
chromatography (TLC) was performed on aluminum-backed 0.20 mm
silica gel plates. Visualization was accomplished with UV light. Flash
chromatography was performed under positive air pressure using Silica
Gel 60 of 230−400 mesh (40−63 μm). Melting points (mp) are
uncorrected. Proton and carbon magnetic resonance spectra (1H and
13C NMR) were recorded on a 300 or 500 MHz spectrometer, as
(racemic)-2,3-Dihydro-1-phenyl-1H-phosphindole-1-oxide (20).
This was prepared according to General Procedure B using a solution
of POPhCl2 (97.5 mg, 0.50 mmol) in THF (3.61 mL) and a solution
of di-Grignard reagent 14 (0.36 M in THF, 1.39 mL, 0.50 mmol).
Flash chromatography (100% EtOAc to 2% NEt3/EtOAc) gave the
known benzophospholane 20 (99.8 mg, 87%) as a white solid. NMR
data was in good agreement with that previously reported.28a mp 86−
88 °C (lit.28c mp 97−101 °C); TLC (2% NEt3/EtOAc) Rf = 0.29; 1H
NMR (500 MHz, CDCl3) δ 7.66 (t, J = 8.2 Hz, 1H), 7.62−7.48 (m,
4H), 7.47−7.34 (m, 4H), 3.49−3.37 (m, 1H), 3.25−3.14 (m, 1H),
2.54−2.37 (m, 2H); 13C NMR (125 MHz, CDCl3) δ 147.3 (d, J = 30.7
Hz), 133.1 (d, J = 97.7 Hz), 132.5 (d, J = 103.1 Hz), 132.4 (d, J = 2.5
Hz), 131.5 (d, J = 2.9 Hz), 130.2 (d, J = 10.5 Hz), 128.6 (d, J = 9.3
Hz), 128.3 (d, J = 12.0 Hz), 127.5 (d, J = 10.4 Hz), 126.1 (d, J = 11.4
Hz), 27.9 (d, J = 3.9 Hz), 27.8 (d, J = 71.0 Hz); IR (neat) v 3442,
1593, 1434, 1195, 1136, 1115, 777, 765, 742 cm−1; HRMS (ESI) [M +
H]+ calcd for C14H14OP, 229.0782; found, 229.0790.
specified. Spectra were aquired in CDCl3 and are reported relative to
tetramethylsilane (1H: δ = 0.00 ppm) and solvent resonance (13C: δ =
77.0 ppm). 1H NMR data are reported as follows: chemical shift,
multiplicity (abbreviations: d = doublet, dd = doublet of doublets, ddd
= doublet of doublets of doublets, t = triplet, td = triplet of doublets, m
= multiplet), coupling constant (Hz), and integration. Coupling
constants listed in the 13C NMR spectral data refer to coupling
between carbon and phosphorus nuclei. High-resolution mass
spectrometry (HRMS) was performed on a QTOF ESI spectrometer.
Anhydrous tetrahydrofuran was obtained commercially. Di-
Grignard reagents were prepared from Mg flakes that were freshly
washed with 1 M HCl, followed sequentially by washing with water,
EtOH, THF, and Et2O before being dried for 20 min under high
vacuum. 1-Bromo-2-(2-chloroethyl)benzene,38 1-bromo-2-(2-
chloroethyl)naphthalene,31 ( )-trans-4,5-bis(bromomethyl)cyclohex-
1-ene,31 and cis-4,5-bis(bromomethyl)cyclohex-1-ene39 were prepared
according to literature procedures. Phenylphosphonic dichloride
(POPhCl2), tert-butylphosphonic dichloride (PO(t-Bu)Cl2), and
N,N-dimethylphosphoramide dichloride (PO(NMe2)Cl2) were ob-
tained commercially. The remaining phosphonic dichlorides utilized in
Table 2 were prepared from their corresponding known phosphonic
acids via chlorination with oxalyl chloride.25,34 All other reagents and
solvents were obtained reagent grade from commercial sources and
used as received.
General Procedure A for the Preparation of Di-Grignard
Reagents. A dry round-bottomed flask was charged with the
appropriate neat dihalo compound (0.24−0.58 mmol, 1.0 equiv) and
Mg (2.1 equiv).40 The flask was evacuated and refilled with N2 (single
cycle); then, THF was added (0.50 M in dihalo compound), and the
suspension was stirred rapidly for 2 h at a temperature dependent on
the substrate. Aliphatic di-Grignard reagents (10, ( )-16, meso-17, and
18) were prepared at rt, whereas mixed aliphatic/aromatic substrates
(14 and 15) were prepared by gradually heating from rt to 65 °C over
30 min, maintaining this temperature for 1 h, and then returning to rt
over 30 min (for these reactions, the flask was equipped with a
condenser). In each case, titration of the resultant supernatant was
carried out with a 1.00 M solution of 2-butanol in toluene using 1,10-
phenanthroline as indicator41 to determine the total concentration of
organomagnesium species, which was halved to obtain the di-Grignard
reagent concentration quoted in the experimental descriptions below.
General Procedure B for the Synthesis of Cyclic Phosphine
Oxides from Di-Grignard Reagents. To a solution of a phosphonic
dichloride (0.30−0.58 mmol) in the specified volume of THF at −78
°C (liquid N2/EtOAc slush bath) under N2 was added dropwise over 2
min a solution of a freshly titrated di-Grignard reagent (1.0 equiv) in
THF. The resulting solution (generally 0.10 M in both reactants) was
allowed to warm to rt with stirring over 20 h. The reaction was
quenched with water (5 mL); then, saturated NH4Cl (5 mL) was
added, followed by EtOAc (20 mL). The organic layer was separated,
and the aqueous layer was further extracted with EtOAc (2 × 20 mL).
The combined organic extracts were dried (MgSO4) and concentrated
(racemic)-1-Phenyl-2,3-dihydro-1H-benzo[g]phosphindole-1-
oxide (21). This was prepared according to General Procedure B using
a solution of POPhCl2 (113.0 mg, 0.58 mmol) in THF (3.80 mL) and
a solution of di-Grignard reagent 15 (0.29 M in THF, 2.00 mL, 0.58
mmol). Flash chromatography (100% EtOAc to 2% NEt3/EtOAc)
gave the known compound 21 (91.4 mg, 57%) as a white solid.
1
Previously, no H NMR data and only partial 13C NMR data have
been reported for 21. Our 13C NMR data was in good agreement with
the available information.30 mp 177−178 °C (lit.30 mp 200−202 °C);
1
TLC (2% NEt3/EtOAc) Rf = 0.37; H NMR (300 MHz, CDCl3) δ
8.13−8.05 (m, 1H), 7.95 (d, J = 8.4 Hz, 1H), 7.86−7.78 (m, 1H), 7.63
(dd, J = 12.3, 7.3 Hz, 2H), 7.46−7.31 (m, 6H), 3.57−3.38 (m, 1H),
3.37−3.20 (m, 1H), 2.67−2.38 (m, 2H); 13C NMR (75 MHz, CDCl3)
δ 147.9 (d, J = 31.1 Hz), 133.8 (d, J = 96.7 Hz), 133.7 (d, J = 2.7 Hz),
132.5 (d, J = 8.0 Hz), 131.7 (d, J = 9.1 Hz), 131.5 (d, J = 3.0 Hz),
130.1 (d, J = 10.4 Hz), 128.4 (d, J = 12.0 Hz), 128.2 (d, J = 1.6 Hz),
128.0 (d, J = 101.5 Hz), 127.6, 126.1, 125.1 (d, J = 4.8 Hz), 123.8 (d, J
= 12.7 Hz), 28.6 (d, J = 4.6 Hz), 27.9 (d, J = 71.4 Hz); IR (neat) v
2360, 1201, 1186, 1111, 818, 784, 740, 691 cm−1; HRMS (ESI) [M +
H]+ calcd for C18H16OP, 279.0939; found, 279.0931.
(racemic)-trans-2-Phenyl-2,3,3a,4,7,7a-hexahydro-1H-isophos-
phindole 2-Oxide (22). This was prepared according to General
Procedure B using a solution of POPhCl2 (97.5 mg, 0.50 mmol) in
THF (3.20 mL) and a solution of di-Grignard reagent 16 (0.13 M in
THF, 3.85 mL, 0.50 mmol). Flash chromatography (100% EtOAc to
2% NEt3/EtOAc) gave 22 (66.4 mg, 57%) as a white solid. mp 88−92
°C; TLC (2% NEt3/EtOAc) Rf = 0.38; 1H NMR (500 MHz, CDCl3) δ
7.81−7.71 (m, 2H), 7.59−7.45 (m, 3H), 5.72 (s, 2H), 2.56−2.35 (m,
4H), 2.30−2.19 (m, 1H), 2.09−1.98 (m, 1H), 1.98−1.77 (m, 3H),
1.62 (ddd, J = 15.0, 12.5, 7.9 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ
134.4 (d, J = 90.1 Hz), 131.6 (d, J = 2.9 Hz), 129.8 (d, J = 9.9 Hz),
128.6 (d, J = 11.6 Hz), 126.2 (d, J = 1.9 Hz), 126.1 (d, J = 1.9 Hz),
40.4 (d, J = 8.2 Hz), 38.9 (d, J = 7.7 Hz), 37.6 (d, J = 66.4 Hz), 36.9
(d, J = 67.6 Hz), 33.2 (d, J = 9.3 Hz), 33.0 (d, J = 9.8 Hz); IR (neat) v
3408, 2887, 1437, 1223, 1187, 927, 852, 786, 726, 692, 655 cm−1;
HRMS (ESI) [M + H]+ calcd for C14H18OP, 233.1095; found,
233.1087.
(meso)-(2s,3aR,7aS)-2-Phenyl-2,3,3a,4,7,7a-hexahydro-1H-iso-
phosphindole 2-Oxide ((sP)-23) and (meso)-(2r,3aR,7aS)-2-Phenyl-
2,3,3a,4,7,7a-hexahydro-1H-isophosphindole 2-Oxide ((rP)-23). The
D
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Note
title compounds were prepared according to General Procedure B
using a solution of POPhCl2 (58.0 mg, 0.30 mmol) in THF (3.00 mL)
and a solution of di-Grignard reagent 17 (0.06 M in THF, 4.00 mL,
0.24 mmol). Flash chromatography (100% EtOAc to 5% NEt3/
EtOAc) gave (sP)-23 (24.0 mg, 43% based on 17) as a white solid. mp
12.6 Hz), 128.7 (d, J = 10.2 Hz), 128.4 (d, J = 1.4 Hz), 128.0, 127.5 (d,
J = 102.6 Hz), 126.4, 125.1 (d, J = 4.7 Hz), 123.9 (d, J = 12.9 Hz),
123.2 (d, J = 15.2 Hz), 28.7 (d, J = 4.8 Hz), 27.9 (d, J = 71.8 Hz); IR
(neat) v 2975, 2350, 1559, 1507, 1395, 1185, 1123, 1066, 824, 777,
681, 664 cm−1; HRMS (ESI) [M + Na]+ calcd for C18H14(79Br)NaOP,
378.9863; found, 378.9868.
1
76−79 °C; TLC (5% NEt3/EtOAc) Rf = 0.55; H NMR (500 MHz,
CDCl3) δ 7.81−7.74 (m, 2H), 7.55−7.46 (m, 3H), 5.69 (s, 2H),
2.50−2.32 (m, 4H), 2.31−2.20 (m, 2H), 2.17−2.09 (m, 2H), 2.09−
1.99 (m, 2H); 13C NMR (125 MHz, CDCl3) δ 134.9 (d, J = 89.6 Hz),
131.2 (d, J = 2.9 Hz), 129.5 (d, J = 9.6 Hz), 128.3 (d, J = 11.5 Hz),
123.9, 35.1 (d, J = 7.3 Hz), 34.9 (d, J = 66.4 Hz), 27.3 (d, J = 7.7 Hz);
IR (neat) v 3400, 2904, 1653, 1436, 1407, 1180, 911, 845, 792, 744,
717, 696, 661 cm−1; HRMS (ESI) [M + H]+ calcd for C14H18OP,
233.1095; found, 233.1085. Further elution (10% NEt3/EtOAc) gave
(rP)-23 (9.0 mg, 16% based on 17) as an amorphous solid. TLC (5%
(racemic)-1-(1-Naphthyl)-2,3-dihydro-1H-benzo[g]-
phosphindole-1-oxide (27). This was prepared according to General
Procedure B using a solution of PO(1-naphthyl)Cl2 (122.5 mg, 0.50
mmol) in THF (3.33 mL) and a solution of di-Grignard reagent 15
(0.30 M in THF, 1.67 mL, 0.50 mmol). Flash chromatography (100%
EtOAc to 1% NEt3/EtOAc) gave 27 (129.8 mg, 79%) as a white solid.
1
mp 208−210 °C; TLC (2% NEt3/EtOAc) Rf = 0.77; H NMR (300
MHz, CDCl3) δ 8.68 (d, J = 8.3 Hz, 1H), 8.31 (d, J = 7.5 Hz, 1H),
7.99 (d, J = 8.5 Hz, 1H), 7.95−7.80 (m, 3H), 7.60−7.30 (m, 6H), 7.24
(t, J = 7.7 Hz, 1H), 3.55−3.35 (m, 1H), 3.22−3.04 (m, 1H), 2.74−
2.55 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 147.9 (d, J = 31.1 Hz),
133.8 (d, J = 2.5 Hz), 133.7 (d, J = 8.7 Hz), 132.8 (d, J = 9.1 Hz),
132.6 (d, J = 2.7 Hz), 132.5, 132.4, 131.5 (d, J = 11.2 Hz), 129.5 (d, J
= 93.7 Hz), 128.9, 128.4 (d, J = 1.5 Hz), 127.83, 127.82 (d, J = 103.5
Hz), 127.3, 126.3, 126.2, 125.9 (d, J = 5.4 Hz), 125.6 (d, J = 4.6 Hz),
124.4 (d, J = 13.8 Hz), 124.1 (d, J = 12.7 Hz), 28.7 (d, J = 4.9 Hz),
28.4 (d, J = 70.6 Hz); IR (neat) v 2990, 1507, 1199, 1187, 1160, 1058,
872, 836, 801, 775, 732, 702, 672 cm−1; HRMS (ESI) [M + Na]+ calcd
for C22H17NaOP, 351.0915; found, 351.0904.
1
NEt3/EtOAc) Rf = 0.18; H NMR (500 MHz, CDCl3) δ 7.83−7.75
(m, 2H), 7.57−7.47 (m, 3H), 5.64 (s, 2H), 2.78−2.66 (m, 2H), 2.37−
2.27 (m, 2H), 2.24−2.12 (m, 2H), 2.11−2.02 (m, 2H), 1.94−1.85 (m,
2H); 13C NMR (125 MHz, CDCl3) δ 134.6 (d, J = 90.0 Hz), 131.6 (d,
J = 2.8 Hz), 130.0 (d, J = 9.7 Hz), 128.7 (d, J = 11.8 Hz), 124.4, 34.2
(d, J = 67.0 Hz), 34.1 (d, J = 7.2 Hz), 27.5 (d, J = 7.9 Hz); IR (neat) v
3407, 2910, 1647, 1436, 1405, 1178, 934, 846, 797, 737, 728, 694, 661
cm−1; HRMS (ESI) [M + H]+ calcd for C14H18OP, 233.1095; found,
233.1095.
1-Phenylphosphinane Oxide (24). This was prepared according to
General Procedure B using a solution of POPhCl2 (97.5 mg, 0.50
mmol) in THF (8.68 mL) and a solution of di-Grignard reagent 18
(0.38 M in THF, 1.32 mL, 0.50 mmol). Flash chromatography (100%
EtOAc to 10% NEt3/EtOAc) gave 24 (34.6 mg, 36%) as a white solid.
NMR data was in good agreement with that previously reported.42 mp
114−117 °C (lit.17a mp 125−127 °C); TLC (2% NEt3/EtOAc) Rf =
(racemic)-1-tert-Butyl-2,3-dihydro-1H-benzo[g]phosphindole-1-
oxide (28). This was prepared according to General Procedure B using
a solution of PO(t-Bu)Cl2 (87.5 mg, 0.50 mmol) in THF (3.21 mL)
and a solution of di-Grignard reagent 15 (0.28 M in THF, 1.79 mL,
0.50 mmol). Flash chromatography (2% NEt3/EtOAc) gave 28 (74.7
mg, 58%) as an off-white solid. mp 138−140 °C; TLC (2% NEt3/
EtOAc) Rf = 0.44; 1H NMR (300 MHz, CDCl3) δ 8.52 (d, J = 8.2 Hz,
1H), 7.93 (d, J = 8.4 Hz, 1H), 7.85 (d, J = 7.8 Hz, 1H), 7.61−7.45 (m,
2H), 7.33 (dd, J = 8.4, 2.3 Hz, 1H), 3.40−3.20 (m, 1H), 3.16−3.01
(m, 1H), 2.62−2.48 (m, 1H), 2.36−2.14 (m, 1H), 1.20 (d, J = 15.0
Hz, 9H); 13C NMR (75 MHz, CDCl3) δ 147.4 (d, J = 28.3 Hz), 133.4
(d, J = 2.8 Hz), 133.2 (d, J = 8.6 Hz), 132.7 (d, J = 7.6 Hz), 128.2,
127.3, 126.6 (d, J = 2.9 Hz), 126.1, 125.3, 123.9 (d, J = 11.7 Hz), 34.9
(d, J = 67.9 Hz), 29.2 (d, J = 4.5 Hz), 24.7 (d, J = 1.4 Hz), 23.4 (d, J =
62.7 Hz); IR (neat) v 2954, 1511, 1464, 1179, 1148, 873, 832, 815,
779, 735, 667, 640 cm−1; HRMS (ESI) [M + Na]+ calcd for
C16H19NaOP, 281.1071; found, 281.1077.
(racemic)-1-Cyclohexyl-2,3-dihydro-1H-benzo[g]phosphindole-1-
oxide (29). This was prepared according to General Procedure B using
a solution of POCyCl2 (77.6 mg, 0.39 mmol) in THF (2.61 mL) and a
solution of di-Grignard reagent 15 (0.31 M in THF, 1.25 mL, 0.39
mmol). Flash chromatography (100% EtOAc to 2% NEt3/EtOAc)
gave 29 (78.9 mg, 72%) as an off-white solid. mp 133−134 °C; TLC
(2% NEt3/EtOAc) Rf = 0.15; 1H NMR (500 MHz, CDCl3) δ 8.44 (d,
J = 8.2 Hz, 1H), 7.91 (d, J = 8.4 Hz, 1H), 7.86 (d, J = 8.2 Hz, 1H),
7.58 (t, J = 7.6 Hz, 1H), 7.50 (t, J = 7.6 Hz, 1H), 7.32 (d, J = 8.5 Hz,
1H), 3.32 (td, J = 17.0, 10.0 Hz, 1H), 3.15−3.02 (m, 1H), 2.55−2.44
(m, 1H), 2.29−2.08 (m, 3H), 1.87−1.76 (m, 1H), 1.76−1.58 (m, 3H),
1.45−1.31 (m, 1H), 1.31−1.10 (m, 4H); 13C NMR (125 MHz,
CDCl3) δ 146.7 (d, J = 28.6 Hz), 133.1 (d, J = 2.8 Hz), 132.7 (d, J =
8.7 Hz), 132.4 (d, J = 7.7 Hz), 128.3 (d, J = 1.0 Hz), 127.5, 127.0 (d, J
= 93.5 Hz), 126.1, 125.5 (d, J = 3.6 Hz), 123.9 (d, J = 11.9 Hz), 39.9
(d, J = 68.0 Hz), 28.5 (d, J = 4.6 Hz), 26.1 (d, J = 5.5 Hz), 26.0 (d, J =
6.2 Hz), 25.8 (d, J = 1.6 Hz), 25.6 (d, J = 1.7 Hz), 25.4 (d, J = 2.8 Hz),
23.1 (d, J = 65.0 Hz); IR (neat) v 2923, 2845, 1507, 1198, 1175, 828,
809, 779, 740 cm−1; HRMS (ESI) [M + H]+ calcd for C18H22OP,
285.1408; found, 285.1404.
1
0.15; H NMR (300 MHz, CDCl3) δ 7.82−7.70 (m, 2H), 7.57−7.43
(m, 3H), 2.25−1.70 (m, 9H), 1.59−1.41 (m, 1H); 13C NMR (75
MHz, CDCl3) δ 133.2 (d, J = 94.4 Hz), 131.6 (d, J = 2.5 Hz), 129.9
(d, J = 9.2 Hz), 128.6 (d, J = 11.5 Hz), 28.2 (d, J = 65.2 Hz), 26.6 (d, J
= 6.8 Hz), 22.0 (d, J = 5.6 Hz); HRMS (ESI) [M + H]+ calcd for
C11H16OP, 195.0939; found, 195.0946.
(racemic)-1-(2-Methoxyphenyl)-2,3-dihydro-1H-benzo[g]-
phosphindole-1-oxide (25). This was prepared according to General
Procedure B using a solution of PO(2-OMePh)Cl2 (71.9 mg, 0.32
mmol) in THF (2.13 mL) and a solution of di-Grignard reagent 15
(0.30 M in THF, 1.07 mL, 0.32 mmol). Flash chromatography (100%
EtOAc to 2% NEt3/EtOAc) gave 25 (51.2 mg, 52%) as an off-white
1
solid. mp 168−169 °C; TLC (2% NEt3/EtOAc) Rf = 0.27; H NMR
(500 MHz, CDCl3) δ 8.16 (dd, J = 13.2, 7.7 Hz, 1H), 8.10 (dd, J = 6.2,
3.4 Hz, 1H), 7.92 (d, J = 8.4 Hz, 1H), 7.85−7.79 (m, 1H), 7.47−7.37
(m, 4H), 7.12 (t, J = 7.5 Hz, 1H), 6.75 (dd, J = 8.3, 5.5 Hz, 1H), 3.55−
3.43 (m, 4H), 3.39−3.29 (m, 1H), 2.74−2.64 (m, 1H), 2.50−2.37 (m,
1H); 13C NMR (125 MHz, CDCl3) δ 160.4 (d, J = 4.5 Hz), 148.0 (d, J
= 33.5 Hz), 134.1 (d, J = 6.2 Hz), 133.7 (d, J = 2.0 Hz), 133.1 (d, J =
2.7 Hz), 132.5 (d, J = 8.1 Hz), 132.0 (d, J = 9.1 Hz), 128.7 (d, J =
104.4 Hz), 128.2 (d, J = 1.4 Hz), 127.5, 125.9, 125.3 (d, J = 4.7 Hz),
123.9 (d, J = 13.3 Hz), 121.4 (d, J = 95.6 Hz), 120.9 (d, J = 11.1 Hz),
110.9 (d, J = 6.3 Hz), 55.3, 29.2 (d, J = 5.1 Hz), 26.7 (d, J = 73.6 Hz);
IR (neat) v 2914, 1589, 1507, 1477, 1273, 1241, 1200, 1148, 1017,
816, 803, 783, 750, 740 cm−1; HRMS (ESI) [M + Na]+ calcd for
C19H17NaO2P, 331.0864; found, 331.0876.
(racemic)-1-(3-Bromophenyl)-2,3-dihydro-1H-benzo[g]-
phosphindole-1-oxide (26). This was prepared according to General
Procedure B using a solution of PO(3-BrPh)Cl2 (136.9 mg, 0.50
mmol) in THF (3.21 mL) and a solution of di-Grignard reagent 15
(0.28 M in THF, 1.79 mL, 0.50 mmol). Flash chromatography (100%
EtOAc to 2% NEt3/EtOAc) gave 26 (88.3 mg, 49%) as a white solid.
(racemic)-1-Allyl-2,3-dihydro-1H-benzo[g]phosphindole-1-oxide
(30). This was prepared according to General Procedure B using a
solution of PO(allyl)Cl2 (79.5 mg, 0.50 mmol) in THF (4.95 mL) and
a solution of di-Grignard reagent 15 (0.29 M in THF, 1.72 mL, 0.50
mmol). Flash chromatography (100% EtOAc to 5% NEt3/EtOAc)
gave 30 (75.3 mg, 62%) as a pale yellow gum. TLC (2% NEt3/EtOAc)
1
mp 114−116 °C; TLC (2% NEt3/EtOAc) Rf = 0.45; H NMR (500
MHz, CDCl3) δ 8.09−8.03 (m, 1H), 7.99 (d, J = 8.5 Hz, 1H), 7.89−
7.80 (m, 2H), 7.57 (d, J = 8.1 Hz, 1H), 7.52−7.40 (m, 4H), 7.27−7.21
(m, 1H), 3.58−3.46 (m, 1H), 3.39−3.26 (m, 1H), 2.65−2.42 (m, 2H);
13C NMR (125 MHz, CDCl3) δ 148.2 (d, J = 31.7 Hz), 136.7 (d, J =
93.4 Hz), 134.7 (d, J = 2.6 Hz), 134.2 (d, J = 2.6 Hz), 133.0 (d, J =
11.1 Hz), 132.7 (d, J = 7.8 Hz), 131.7 (d, J = 9.0 Hz), 130.2 (d, J =
1
Rf = 0.10; H NMR (500 MHz, CDCl3) δ 8.44 (d, J = 8.3 Hz, 1H),
7.94 (d, J = 8.4 Hz, 1H), 7.89 (d, J = 8.2 Hz, 1H), 7.61 (t, J = 7.6 Hz,
E
DOI: 10.1021/acs.joc.5b01476
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
1H), 7.53 (t, J = 7.8 Hz, 1H), 7.33 (dd, J = 8.5, 2.3 Hz, 1H), 5.60−5.50
(m, 1H), 5.12−5.03 (m, 2H), 3.36 (td, J = 16.7, 10.0 Hz, 1H), 3.15−
2.96 (m, 3H), 2.53−2.45 (m, 1H), 2.36−2.23 (m, 1H); 13C NMR
(125 MHz, CDCl3) δ 146.5 (d, J = 30.3 Hz), 133.3, 132.4 (d, J = 7.7
Hz), 132.1 (d, J = 9.1 Hz), 128.4, 127.7, 127.6 (d, J = 104.6 Hz), 127.3
(d, J = 7.9 Hz), 126.2, 124.9 (d, J = 4.1 Hz), 123.8 (d, J = 12.4 Hz),
119.9 (d, J = 11.8 Hz), 37.0 (d, J = 62.4 Hz), 28.4 (d, J = 4.6 Hz), 24.2
(d, J = 68.9 Hz); IR (neat) v 3410, 2927, 1510, 1204, 1176, 1150,
1116, 1010, 924, 818, 749 cm−1; HRMS (ESI) [M + Na]+ calcd for
C15H15NaOP, 265.0758; found, 265.0759.
(racemic)-1-Dimethylamino-2,3-dihydro-1H-benzo[g]-
phosphindole-1-oxide (31). This was prepared according to General
Procedure B using a solution of PO(NMe2)Cl2 (81.0 mg, 0.50 mmol)
in THF (3.33 mL) and a solution of di-Grignard reagent 15 (0.30 M
in THF, 1.67 mL, 0.50 mmol). In this case, due to the potential
susceptibility of the NMe2 group to hydrolysis, the reaction was
quenched by the addition of crushed ice (5 g) instead of water.
Otherwise, workup was performed as described. Flash chromatography
(2% NEt3/EtOAc) gave 31 (107.9 mg, 88%) as an off-white solid. mp
123−125 °C; TLC (2% NEt3/EtOAc) Rf = 0.17; 1H NMR (500 MHz,
CDCl3) δ 8.28 (d, J = 8.3 Hz, 1H), 7.89 (d, J = 8.5 Hz, 1H), 7.84 (d, J
= 8.3 Hz, 1H), 7.56 (t, J = 7.7 Hz, 1H), 7.48 (t, J = 7.7 Hz, 1H), 7.29
(d, J = 7.8 Hz, 1H), 3.32−3.20 (m, 1H), 3.20−3.08 (m, 1H), 2.61 (d, J
= 10.4 Hz, 6H), 2.26−2.12 (m, 2H); 13C NMR (75 MHz, CDCl3) δ
147.4 (d, J = 35.3 Hz), 133.1 (d, J = 2.8 Hz), 132.3 (d, J = 7.6 Hz),
131.5 (d, J = 8.4 Hz), 128.1 (d, J = 1.2 Hz), 127.4, 126.4 (d, J = 117.9
Hz), 126.0, 124.9 (d, J = 4.5 Hz), 124.1 (d, J = 13.8 Hz), 35.2 (d, J =
4.1 Hz), 26.9 (d, J = 6.8 Hz), 22.1 (d, J = 85.8 Hz); IR (neat) v 2910,
1507, 1455, 1282, 1199, 974, 824, 752, 601, 647 cm−1; HRMS (ESI)
[M + Na]+ calcd for C14H16NNaOP, 268.0867; found, 268.0862.
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.joc.5b01476.
■
S
1H and 13C NMR spectra for all compounds, selected
gCOSY and gHSQC NMR spectra, and X-ray crystallo-
graphic information for compounds (sP)-23 and 27
(PDF, CIF, CIF).
AUTHOR INFORMATION
Corresponding Author
*E-mail: keller@uow.edu.au.
■
(17) (a) Wetzel, R. B.; Kenyon, G. L. J. Org. Chem. 1974, 39, 1531−
1535. (b) Davies, J. H.; Downer, J. D.; Kirby, P. J. Chem. Soc. C 1966,
245−247.
Author Contributions
§A.M.G., S.M.W., and S.J.B. contributed equally to this work.
Notes
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The authors declare no competing financial interest.
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G
DOI: 10.1021/acs.joc.5b01476
J. Org. Chem. XXXX, XXX, XXX−XXX