Biphilic Organophosphorus-Catalyzed Intramolecular Csp2-H Amination: Evidence for a Nitrenoid in Catalytic Cadogan Cyclizations

Article abstract of DOI:10.1021/jacs.7b13803

A small-ring phosphacycloalkane (1,2,2,3,4,4-hexamethylphosphetane, 3) catalyzes intramolecular C-N bond forming heterocyclization of o-nitrobiaryl and -styrenyl derivatives in the presence of a hydrosilane terminal reductant. The method provides scalable access to diverse carbazole and indole compounds under operationally trivial homogeneous organocatalytic conditions, as demonstrated by 17 examples conducted on 1 g scale. In situ NMR reaction monitoring studies support a mechanism involving catalytic P^III/P^V=O cycling, where tricoordinate phosphorus compound 3 represents the catalytic resting state. For the catalytic conversion of o-nitrobiphenyl to carbazole, the kinetic reaction order was determined for phosphetane catalyst 3 (first order), substrate (first order), and phenylsilane (zeroth order). For differentially 5-substituted 2-nitrobiphenyls, the transformation is accelerated by electron-withdrawing substituents (Hammett factor ? = +1.5), consistent with the accrual of negative charge on the nitro substrate in the rate-determining step. DFT modeling of the turnover-limiting deoxygenation event implicates a rate-determining (3 + 1) cheletropic addition between the phosphetane catalyst 3 and 2-nitrobiphenyl substrate to form an unobserved pentacoordinate spiro-bicyclic dioxazaphosphetane, which decomposes via (2 + 2) cycloreversion giving 1 equiv of phosphetane P-oxide 3·[O] and 2-nitrosobiphenyl. Experimental and computational investigations into the C-N bond forming event suggest the involvement of an oxazaphosphirane (2 + 1) adduct between 3 and 2-nitrosobiphenyl, which evolves through loss of phosphetane P-oxide 3·[O] to give the observed carbazole product via C-H insertion in a nitrene-like fashion.

Full text of DOI:10.1021/jacs.7b13803

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Article
Biphilic Organophosphorus-Catalyzed Intramolecular Csp2-H
Amination: Evidence for a Nitrenoid in Catalytic Cadogan Cyclizations
Trevor V. Nykaza, Antonio Ramirez, Tyler S. Harrison, Michael R Luzung, and Alexander T. Radosevich
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.7b13803 • Publication Date (Web): 01 Feb 2018
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Biphilic Organophosphorus-Catalyzed Intramolecular Csp2-H Ami-
nation: Evidence for a Nitrenoid in Catalytic Cadogan Cyclizations
Trevor V. Nykaza,† Antonio Ramirez,‡ Tyler S. Harrison,† Michael R. Luzung,*‡ Alexander T. Radose-
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vich*†
†Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, United States
‡Chemical and Synthetic Development, Bristol-Myers Squibb Company, One Squibb Drive, New Brunswick, New Jersey
08903, United States
ABSTRACT: A small-ring phosphacycloalkane (1,2,2,3,4,4-hexamethylphosphetane, 3) catalyzes intramolecular C–N bond forming
heterocyclization of o-nitrobiaryl and –styrenyl derivatives in the presence of a hydrosilane terminal reductant. The method provides
scalable access to diverse carbazole and indole compounds under operationally trivial homogeneous organocatalytic conditions, as
demonstrated by 17 examples conducted on one-gram scale. In situ NMR reaction monitoring studies support a mechanism involving
catalytic PIII/PV=O cycling, where tricoordinate phosphorus compound 3 represents the catalytic resting state. For the catalytic con-
version of o-nitrobiphenyl to carbazole, the kinetic reaction order was determined for phosphetane catalyst 3 (first order), substrate
(first order), and phenylsilane (zeroth order). For differentially 5-substituted 2-nitrobiphenyls, the transformation is accelerated by
electron–withdrawing substituents (Hammett factor ρ = +1.5), consistent with the accrual of negative charge on the nitro substrate in
the rate-determining step. DFT modeling of the turnover-limiting deoxygenation event implicates a rate-determining (3+1)
cheletropic addition between the phosphetane catalyst 3 and 2-nitrobiphenyl substrate to form an unobserved pentacoordinate spiro-
bicyclic dioxazaphosphetane, which decomposes via (2+2) cycloreversion giving one equivalent of phosphetane P-oxide 3•[O] and
2-nitrosobiphenyl. Experimental and computational investigations into the C–N bond forming event suggest the involvement of an
oxazaphosphirane (2+1) adduct between 3 and 2-nitrosobiphenyl, which evolves through loss of phosphetane P-oxide 3•[O] to give
the observed carbazole product via C–H insertion in a nitrene-like fashion.
1. INTRODUCTION
perstoichiometric amounts of phosphorus-based reagents at el-
evated temperatures (typically neat refluxing triethylphosphite),
although milder conditions11 or alternative stoichiometric rea-
gents12 have been applied in some cases. The process mass in-
tensity and inherent inefficiencies of the stoichiometric Ca-
dogan method have been persistent drawbacks that have limited
its use on large synthetic scales.13
Nitrogen containing heterocyclic compounds, such as carba-
zoles and indoles, are important synthetic targets due to their
prevalence in bioactive natural metabolites and pharmaceuti-
cals,1 as well as their application in functional optoelectronic
materials.2 Accordingly, numerous synthetic methods exist for
their production. Among the methods to synthesize carba-
zoles1a,3 and indoles,4 those involving direct cyclization via C–
H amination are attractive.5 The carbazole-/indole-forming
method of Sundberg, involving heterocyclization by thermoly-
sis or photolysis of o-azidonitrobiaryls and o-azidostyrenes and
proceeding via an arylnitrene C–H insertion pathway,6 exempli-
fies the efficiency of this bond construction (Figure 1A). Tran-
sition metal catalysts have more recently been found to bring
about similar transformations of such azide substrates under
milder thermal conditions,7 although the inherent hazards asso-
ciated with the preparation and handling of azide containing in-
termediates represent a practical constraint for such protocols
on process synthesis scales.8
Catalytic variants of Cadogan-like reductive cyclizations of ni-
troarenes have been developed that in part address these chal-
lenges. For instance, numerous reports have described the use
of palladium catalysis in conjunction with CO as a terminal re-
ductant to achieve intramolecular heterocyclization of nitro
substrates (Figure 1B).14 Despite the laboratory scale appeal of
these synthetically useful methods, the difficulty of purging
Lewis acidic metal catalysts from the nitrogen-rich products of
cyclization and the use of pressurized carbon monoxide as a ter-
minal reductant (which triggers the need for specialized reactors
and safety protocols, especially in kilo lab and pilot plant set-
tings) increase the operational complexity of synthetic routes in
which these methods are employed. A notable exception in this
latter regard is a recent report from Driver,15 who has developed
an iron-hydride catalyzed synthesis of carbazoles and related
derivatives in which the terminal reductant is a relatively innoc-
uous liquid hydrosilane.
By way of complement, Cadogan has extensively documented
that qualitatively similar azacyclizations can be driven by phos-
phine-mediated exhaustive deoxygenation of o-functionalized
nitrobenzene derivatives (Figure 1A).9 Chief advantages of this
chemistry comprise the ease with which the aryl nitro moiety is
installed and transformed in synthesis,10 including its orthogo-
nality with respect to many transition metal catalyzed chemis-
tries. In common practice, Cadogan transformations employ su-
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2. RESULTS
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2.1 Optimization of Reaction Conditions.
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Consistent with observations made during the discovery of our
previously reported catalytic N–N bond forming Cadogan inda-
zolation, reaction of o-nitrobiphenyl 1 with a substoichiometric
amount (15 mol%) of methyl phosphetane P-oxide 3•[O] and
phenylsilane (2 equiv) produced carbazole product 2 with a GC
yield of 84% after 16 h at 100 °C (Table 1, entry 1). Alteration
of the exocyclic P-substituent was found to lower the catalytic
reactivity; significantly lower yields were obtained under oth-
erwise identical conditions for P-phenyl phosphetane 4•[O] (en-
try 2) and P-pyrrolidino phosphetane 5•[O] (entry 3). Control
experiments demonstrate that the reaction does not occur when
either the precatalyst 3•[O] (entry 4) or phenylsilane terminal
reductant (entry 5) are omitted. Furthermore, the use of 15
mol% of PIII phosphetane 3 as catalyst in the presence of
phenylsilane reductant produced a qualitatively similar amount
of carbazole 2 (entry 6) as when 3•[O] is employed (entry 1),
consistent with notion of catalysis involving cycling between
PIII/PV=O species.
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Figure 1. Intramolecular Csp2–H amination reactions. (A) Classical
Sundberg and Cadogan reactions. (B) Transition metal catalyzed
carbazole-/indole-formation. (C) Catalytic Cadogan cyclization op-
erating through a PIII/PV=O redox cycle.
Our group has been pursuing a program aimed at developing
designer main group compounds as biphilic16 organocatalysts in
organic synthesis.17 In this vein, we recently reported that a sim-
ple trialkylphosphine catalyst containing a core four-membered
ring, in combination with phenylsilane as a terminal reductant,
provided a competent system for the catalytic reductive N–N
bond forming heterocyclization of o-nitrobenzaldimines giving
2H-indazoles.18 In this chemistry, the phosphacyclic catalyst
promotes reductive O-atom transfer from the nitroarene sub-
strates by cycling in the PIII/PV=O catalytic couple. The varied
catalytic chemistry of phosphine oxides is experiencing rapid
expansion,19 and the potential of PIII/PV=O redox methods20 in
particular to favorably impact the process intensity of otherwise
stoichiometric phosphorus-mediated transformations has been
specifically noted.21
The four-membered phosphacycle of catalysts 3/3•[O] appears
crucial for efficient carbazole formation. Five-membered ring
containing phospholane-based precatalysts (6•[O] and 7•[O],
entries 7, 8), which have previously been applied to catalytic
PIII/PV=O Wittig20a,c,d,g-i and Appel20b reactions, gave low yield
of carbazole 2. Moreover, acyclic phosphine oxides (8•[O],
9•[O], and 10•[O], entries 9–11) exhibited poor catalytic reac-
tivity.
Table 1. Phosphacycles as Catalysts for Deoxygenative Het-
erocyclization of o-Nitrobiphenyl 1.a
Based on this precedent, we wished to ascertain whether the re-
active intermediates generated from nitroarenes under PIII/PV=O
catalytic conditions would be applicable to the construction of
C–N bonds in an intramolecular Cadogan-like manner (Figure
1C). In this study, we report the discovery, development, and
mechanistic evaluation of such a new biphilic organophospho-
rus-catalyzed method for carbazole and indole synthesis. The
key features of the system we describe here include: (1) a prac-
tical, scalable, and operationally robust organophosphorus-cat-
alyzed protocol for C–H functionalizing Cadogan azacycliza-
tions that greatly simplifies product isolation for this class of
reactions, (2) a combined experimental and computational as-
sessment of the reaction mechanism for nitro deoxygenation
and subsequent C–N bond formation that provides evidence for
the controlling role of P-based biphilic reactivity in these cata-
lytic Cadogan cyclizations, and (3) spectroscopic evidence for
a heretofore unobserved adduct of a tricoordinate phosphorus
compound and a nitrosoarene that we propose serves as the im-
mediate precursor to C–H amination in the catalytic transfor-
mation. Taken together, these findings enrich fundamental un-
derstanding of the intermediate speciation in phosphine/ni-
troarene reactions and advance the biphilic reactivity of phos-
phetanes as generalized platforms for catalytic reductive O-
atom transfer operating in the PIII/PV=O redox manifold.
Entry
R3P=O
3•[O]
4•[O]
5•[O]
none
Silane
PhSiH3
PhSiH3
PhSiH3
PhSiH3
none
Conversion (%) Yield (%)
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2
99
30
18
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13
94
81
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84
23
7
3
4
0
5
3•[O]
3
0
6
PhSiH3
PhSiH3
PhSiH3
PhSiH3
PhSiH3
PhSiH3
86
20
0
7
6•[O]
7•[O]
8•[O]
9•[O]
10•[O]
8
9
14
35
1
12
20
0
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a Yields reported for isolated products. b (EtO)3SiH (4 equiv) was
12b
3•[O]
PhSiH3
99
93
used as reductant. See Supporting Information for full experimental
details.
a Conversion and yield determined via GC vs internal standard (do-
decane). b Reaction conducted in n-butyl acetate (1.0 M) at 120 °C
with 20 mol% 3•[O] for 12 h.
catalytic protocol compares favorably with the commonly em-
ployed stoichiometric Cadogan methods used for preparation of
this fragment. Complementarily, 2,7-substituted carbazoles
bearing electron-withdrawing groups were also produced in
good yield, albeit in somewhat lower overall yield (compare 13
and 2).23 Variation of the biaryl core provides access to related
heterocarbazole derivatives, as in the functionalized δ-car-
bolines 14-17. Both electron-withdrawing (14-16) and electron-
donating substituents (17) are tolerated without incident. Fused
polyheterocyclic compounds, including 7H-pyridocarbazole
(18), are also capable of being prepared in good yield from the
5-aryl quinoline starting material.
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9
The catalytic reaction is tolerant of varied reaction solvents, and
further optimization studies converged on conditions using 20
mol% of 3•[O] and 2 equiv of phenylsilane at 120 °C in n-butyl
acetate, which gave excellent conversion to carbazole 2 (entry
12). A practical advantage of these conditions and the use of the
low-volatility, process-scalable n-butyl acetate solvent22 is that
carbazole product 2 precipitates from the homogeneous cata-
lytic reaction mixture upon cooling and can be collected in
>98% purity (HPLC) by filtration in a straightforward fashion.
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2.2 Reaction Scope
2.2.2 Synthesis of indoles and related heterocycles. The cata-
lytic protocol can be similarly applied to form indoles from var-
ious o-nitrostyrene compounds on a one-gram scale, although
silica gel column chromatography proved to be more conven-
ient for isolation of these examples (Table 3). It was found that
2-substituted aryl indoles can be easily accessed under standard
reaction conditions, providing 2-phenyl (19, 21) and 2-mesityl
(20) indole products with good yield. Nitrostyrene substrates
bearing α-aliphatic, α,β-aliphatic, and α,β-aromatic moieties
were found to similarly cyclize to give the corresponding 3-sub-
stituted (22) and 2,3-disubstituted (23, 24) indole products with-
out incident. Additionally, 2-(2’-nitrophenyl)thiophene was cy-
clized to give 4H-thieno[3,2-b]indole (25) in good yield. A γ-
pyrone bearing substrate was also readily cyclized to give py-
rano[3,2-b]indole (26) in modest yield, which can be easily con-
verted to the naturally occurring alkaloid koniamborine via N-
methylation.24 Biindole (27) could be prepared following
mono-cyclization of (E)-3-(2-nitrostyryl)-1H-indole using our
catalytic reaction conditions.
2.2.1 Synthesis of carbazoles and related heterocycles. An in-
vestigation of the scope of the catalytic carbazole synthesis was
undertaken, with results collected in Table 2. In view of the pro-
cedural simplicity of the catalytic protocol, we elected to con-
duct all of these examples on one-gram scale; the products re-
ported in Table 2 were obtained in excellent purity by simple
filtration and washing. In these experiments, no special precau-
tions were employed to exclude air or moisture from the reac-
tion; all reagents and solvents were commercial grade and
charged to the reaction vessel under ambient atmosphere. In this
manner, a variety of natural and unnatural carbazoles may be
prepared in a useful manner. Methoxycarbazole natural prod-
ucts glycoborine (11) and clausine V (12) are representative ex-
amples, with isolated yields of 77% and 75%, respectively. We
note that the 2,7-dialkoxycarbazole motif as in 12 has found ap-
plications in electrochromic and optoelectronic materials, and
the current
Table 2. Examples of Catalytic Carbazole Synthesis.a
Table 3. Examples of Catalytic Indole Synthesis.a
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a Yields reported for isolated products. b Reaction was run on a half-
3•[O], 2 equiv of phenylsilane, 1 M in n-butyl acetate, 118 ± 2
gram scale. See Supporting Information for full experimental de-
tails.
1
2
°C) was monitored quantitatively via ex situ HPLC analysis of
reaction aliquots drawn at intervals over the course of 5 h.
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2.3 Mechanistic Investigations
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2.3.1 In situ spectral monitoring under catalytic conditions. In
situ spectral monitoring of the catalytic reaction was performed
in order to gain insight into the reaction mechanism and to can-
(1)
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1
From the chromatograms (see Supporting Information), starting
material 1 is converted to carbazole product 2 in >95 % effi-
ciency. Plots depicting the depletion in concentration of starting
material 1 as a function of time are fit by a model describing
first order dependence in 1 (Figure 3A). The initial rates ob-
tained via this method vary linearly with precatalyst 3•[O] con-
centration in the range 0.02 M ≤ [3•[O]] ≤ 0.08 M (Figure 3C),
indicating that the reaction in eq 1 is pseudo-first order in
precatalyst 3•[O]. Rate constants obtained by the complemen-
tary monitoring of increasing product 2 concentration with time
at varying precatalyst 3•[O] concentrations (Figure 3B) agree
within ±10%. Initial reaction rates measured for this same cata-
lytic reaction do not vary as a function of phenylsilane concen-
tration in the range 0.2 M–0.6 M (Figure 3D), and therefore the
reaction rate is zeroth order in phenylsilane within this concen-
tration regime. Taken together, the empirical rate law for the
catalytic Cadogan cyclization o-nitrobiphenyl may be described
as in eq 2:
vass for catalytic intermediates. H NMR spectra (400 MHz,
100 °C) of a catalytic reaction (1 equiv of 1, 20 mol% of 3•[O],
2 equiv of phenylsilane, 1 M in toluene-d8) showed consump-
tion of 2-nitrobiphenyl 1 over ca. 4 h with concomitant appear-
ance of carbazole 2 as the major product. 31P NMR spectra col-
lected under identical conditions showed that phosphetane
3•[O] (δ 53.5 ppm) is rapidly consumed (t1/2~5 min), giving rise
to two new resonances at δ 32.5 and δ 19.0 ppm in a 5:1 ratio
(Figure 2). Independent synthesis confirms that these signals
correspond to the diastereomers of tricoordinate phosphetane 3
(δ 32.5 (major, anti); δ 19.0 ppm (minor, syn)). In accord with
extensive literature precedent,25 the lack of stereospecificity in
the phosphetane P-oxide reduction event is taken to be indica-
tive of the intermediacy of a pentacoordinate phosphorane with
a sufficient lifetime during hydrosilane-mediated phosphine ox-
ide reduction to permit pseudorotation leading to stereochemi-
cal scrambling.
ν = kexpt[1]1[3•[O]]1[PhSiH3]0
(2)
Figure 2. Time-stacked in situ 31P NMR spectra during catalysis
(T = 100 °C, toluene-d8). (A) t = 0 min; (B) t = 5 min; (C) t = 30
min; (D) t = 60 min. Chemical shifts (δ): anti-3•[O], 53.5 ppm;
anti-3, 32.5 ppm; syn-3, 19.0 ppm.
As the catalytic conversion of 1 continues, the tricoordinate ep-
imers of 3 remain the only observable phosphorus-containing
compounds in solution. Evidently, tricoordinate 3 represents the
catalytic resting state. When taken together, it can be inferred
from the 1H and 31P NMR data that the turnover-limiting step in
the catalytic formation of carbazole 2 involves an initial reac-
tion of substrate 1 with tricoordinate phosphetane 3, and that
phosphine oxide reduction of 3•[O] is more rapid than O-atom
transfer to 3 from the 2-nitrobiphenyl substrate 1.
Figure 3. Kinetics experiments of catalytic reductive cyclization.
(a) concentration of substrate 1 vs time; (b) concentration of prod-
uct 2 vs time; (c) plot of initial rates of substrate 1 consumption vs
concentration of precatalyst 3•[O]; (d) plot of observed initial rates
of substrate 1 consumption vs phenylsilane concentration.
2.3.3 Hammett linear free energy relationship. In order to eval-
uate the electronic demand of the reaction, a panel of electroni-
cally varied 5-substituted 2-nitrobiphenyl compounds (1a–e)
2.3.2 Catalytic reaction kinetics. The kinetic progress of stand-
ard catalytic reaction (eq 1; conditions: 1 equiv of 1, 20 mol%
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As in the stoichiometric studies, a positive Hammett sensitivity
were treated under pseudo-first order conditions with an excess
1
2
3
4
5
6
7
of phosphetane 3, and the rates of conversion to the correspond-
ing carbazoles (2a–e) were monitored over time relative to an
internal standard (1,3,5-trimethoxybenzene) via 1H NMR spec-
troscopy (eq 3).
constant identical within experimental error (ρ = +1.55) was ob-
tained for the catalytic reaction (see Figure S1). This result ad-
duces evidence that both the stoichiometric and catalytic reac-
tions proceed in a mechanistically consistent manner in which
the tricoordinate phosphetane 3 engages the nitroarene substrate
in a rate-determining step involving net transferal of electron-
density from the phosphorus compound to the nitro substrate.
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9
2.3.4 Studies on nitrosobiaryl substrates. Despite the apparent
absence of detectable intermediates during in situ spectroscopic
monitoring, it seemed reasonable to consider the potential inter-
mediacy of 2-nitrosobiphenyl (28). Previous studies on reduc-
tive nitroarene transformations have considered nitrosoarenes
to be obligate intermediates, and Cadogan has specifically
shown the stoichiometric conversion of 2-nitrosobiphenyl to
carbazole with P(OEt)3.28 A control experiment in which 2-ni-
trosobiphenyl (28) was subjected to catalytic conditions (eq 5)
was found to produce 67% of carbazole 2 in addition to 11% of
2-aminobiphenyl (29). This result suggests that 2-nitrosobi-
phenyl is indeed a viable intermediate en route to carbazole un-
der catalytic conditions, although alternative pathways compete
at the relatively high concentrations of 28 in eq 5. The origin of
the reduced product 29 remains a topic of investigation.
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(3)
Qualitatively, a clear trend in relative rates for carbazole for-
mation was observed, with substrates bearing electron-with-
drawing 5-substituents proceeding to product more swiftly than
those with electron-donating 5-substituents. A plot of log(kX/kH)
versus substituent constant σp gives a good linear fit (Figure 4),
from which a Hammett sensitivity constant ρ = +1.55 may be
derived. Evidently, the rate-determining transition structure for
the transformations 1a-e to 2a-e is one in which partial negative
charge accrues to the nitroarene moiety as might be expected
for a reaction that reduces the oxidation state of the nitrogen
center. These data are consistent with linear free energy rela-
tionships obtained by Sundberg26 and Cadogan27 with tri-
ethylphosphite and related P(III) reagents.
(5)
In an attempt to further investigate the reaction of 2-nitro-
sobiphenyl (28) with phosphetane 3, low temperature VT-NMR
studies were conducted. In a representative experiment (eq 6),
a toluene-d8 solution of 3 (0.13 M) was frozen in liquid nitro-
gen, and a cold (–78 °C) solution of 2-nitrosobiphenyl (28, 0.11
M, 1.3 equiv) was layered on top via syringe injection.
(6)
Figure 4. Hammett plot for carbazole formation mediated by 3 ac-
cording to the reaction depicted in eq 3. Equation: y = 1.552x –
0.046; R2 = 0.9978.
The resulting heterogeneous mixture was inserted into a –60 °C
thermostatted NMR probe, where it underwent thawing and
slow diffusional mixing over the course of ca. 80 min. 31P NMR
spectra (Figure 5) recorded subsequently at 10 min intervals
showed the initial consumption of the starting tricoordinate
phosphetane 3 (δ 24.2 major, 11.3 minor ppm)29 and conversion
to two new resonances with an upfield chemical shift (δ –24.4
major, –21.8 minor ppm). At subsequent time points, the reso-
nances from these intermediates diminished, concomitant with
growth of signals corresponding to 3•[O] (δ 54.1 major, 61.8
minor ppm). Upon termination of the NMR experiment, an ali-
quot of the mixture was submitted to GCMS analysis, which
showed the presence of phosphetane P-oxide 3•[O] and carba-
zole 2 as the only observable products.
To compare this stoichiometric linear free energy relationship
to one under catalytic conditions, the identical substrate set was
transformed by reaction with 20 mol% 3•[O], 2 equiv of
phenylsilane, at 100 °C in toluene-d8 (eq 4).
(4)
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theory (Figure 6C), and the magnetic shielding tensors for these
1
2
3
4
5
6
7
8
species were computed by the gauge-independent atomic or-
bital (GIAO) routine at the PBE1PBE/6-311G(2d,2p) level. The
predicted isotropic chemical shifts for anti-30 and syn-30 (δ –
26.8 and –28.8 ppm, respectively) are in good agreement with
the observed signals in the low temperature 31P NMR spectra
depicted in Figure 6. As a further measure of confidence in the
predicted NMR shift for 30, we similarly computed GIAO 31P
NMR chemical shifts for the epimers of 3 and 3•[O], whose
structures and spectra are independently known from experi-
ment (Table 4). The linear correlation between observed and
calculated 31P NMR chemical shifts (Figure S7) provides an in-
ternal validation that the GIAO routine renders a quality de-
scription (average error of δ ±5 ppm) of the isotropic chemical
shift in this series of experimentally relevant phosphetane com-
pounds. The general suitability of GIAO-DFT methods for the
prediction of 31P NMR chemical shifts has recently been ana-
lyzed by Latypov and coworkers.32
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Figure 5. Time-stacked in situ 31P NMR spectra of the reaction of
phosphetane 3 and 2-nitrosobiphenyl 28 (–60 °C < T < –50 °C, tol-
uene-d8). (A) t = 0 min; (B) t = 120 min; (C) t = 200 min; (D) t =
300 min; (E) t = 390 min. Chemical shifts (δ): anti-3•[O], 54.1 ppm;
syn-3•[O], 61.8 ppm; anti-3, 24.2 ppm; syn-3, 11.3 ppm; syn-30,
−21.8 ppm; anti-30, −24.4 ppm.
Table 4. Experimentala and calculatedb 31P NMR chemical shift
valuesc for 3, 3•[O], and 30.
On the basis of the foregoing experiment, we postulate that the
observed 31P NMR resonance at δ –24.4 ppm corresponds to a
metastable intermediate along the C–N bond forming carbazo-
lation pathway, arising from reaction of phosphetane 3 and 2-
nitrosobiphenyl (28). Furthermore, reaction between phos-
phetane 3 and isotopically labelled 2-(15N)nitrosobiphenyl
shows that the resonance at δ –24.4 ppm exhibits 31P–15N scalar
coupling with J = 40.8 Hz (Figure 6A). The magnitude of this
coupling constant falls within the expected range for direct one-
bond 1JPN coupling,30 and the upfield 31P chemical shift is most
consistent with a formulation as a pentacoordinate phosphorane
Chemical shift (δ)c
Compound
expta
+11.3
+24.2
+61.8
+54.1
–21.8
–24.4
calcb
+14.3
+24.2
+52.0
+54.0
–28.8
–26.8
syn-3
anti-3
syn-3•[O]
anti-3•[O]
syn-30
b,
31
species.17 A complementary doublet centered at δ 239 ppm
(J = 40.6 Hz) is observed in the 15N NMR spectrum. We there-
fore posit that PV oxazaphosphirane structures 30, as depicted
in eq 6, give rise to the observed intermediate 31P NMR reso-
nances. Compounds 30 would be formed from 3 as two mag-
netically inequivalent stereoisomers (anti-30 and syn-30) that
could account for the observed signals in the heteronuclear
NMR spectra.
anti-30
a Isotropic 31P NMR (161.796 MHz) chemical shift in toluene-d8 at
b
T = –60 °C. GIAO NMR chemical shift at the PBE1PBE/6-
311G(2d,2p)//M06-2X/6-311++G(d,p) level of theory. c Chemical
shift (δ) in ppm referenced relative to 85% H3PO4 standard (δ = 0.0
ppm).
2.4 Computational Modeling of the Reaction Sequence
2.4.1 DFT studies of the first deoxygenation event – mechanism
of nitroarene deoxygenation. In an effort to gain a more atom-
istic understanding of the mechanism of catalytic Cadogan cy-
clization, potential energy surface modeling of the two sequen-
tial deoxygenations of 2-nitrobiphenyl (1) by phosphetane 3
were conducted at the M06-2X/6-311++G(d,p) level of theory
with a polarizable continuum model (PCM) for solvation in n-
butyl acetate (ε = 4.9941). In accord with our previous calcula-
tions on a related system,18 computational models indicate a
stepwise pathway for the initial deoxygenation of 1 by phos-
phetane 3 proceeding by (3+1) cheletropic addition (TS1, ΔG‡
rel
Figure 6. Heteronuclear NMR spectra of a reaction of phosphetane
3 and 2-(15N)nitrosobiphenyl 28 (–60 °C < T < –50 °C, toluene-d8).
Units are ppm relative to 85% H3PO4 (31P, δ = 0.0 ppm) and liquid
NH3 (15N, δ = 0.0 ppm). (A) Annotated 31P NMR spectrum. (B)
Annotated 15N NMR spectrum. (C) DFT model of oxazaphos-
phiranes 30 (ΔGrel = –0.3 kcal/mol favoring anti-30).
= +30.0 kcal/mol) to form pentacoordinate spiro-bicyclic diox-
azaphosphetane species INT1 (Figures 7 and 8). Both the P–O
(2.39 Å and 2.21 Å) and N–O (1.28 Å and 1.27 Å) bond dis-
tances in TS1 are indicative of a concerted mechanism in which
the phosphorous concurrently attacks the two oxygen atoms of
the nitro group. The heteroatomic ring system of INT1 displays
The geometries of DFT models for diastereomers anti-30 and
syn-30 were optimized at the M06-2X/6-311++G(d,p) level of
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a nearly planar four-membered ring (DPONO = 6.7°) that includes
a square pyramidal phosphorus and a pyramidal nitrogen.
-CF3
0.54
5.67
–1.0
–2.9
1
2
3
4
5
6
7
8
a
b
See Supporting Information for full details. Relative transition
state free energy calculated by M06-2X/6-311++G(d,p). c Units are
kcal/mol at T=298 K.
Subsequent evolution of dioxazaphosphetane INT1 produces
phosphine oxide 3•[O] and 2-nitrosobiphenyl (28) by a retro-
(2+2) fragmentation. This step is computed to be significant
downhill energetically (ΔGrel = –35.8 kcal/mol), with compara-
tively low kinetic barrier via TS2 (ΔG‡rel = +11.8 kcal/mol). The
low activation energy of the cycloreversion is consistent with
ring strain relief and the advanced formation of phosphetane P-
oxide 3•[O].
2.4.2 DFT studies of the second deoxygenation event – mecha-
nism of nitrosoarene deoxygenation and C–N bond formation.
Modeling the deoxygenation of 2-nitrosobiphenyl 28 by phos-
phetane 3 revealed the favorable formation of oxazaphos-
phirane intermediates 30 (ΔGrel = –3.7 kcal/mol for the most
stable anti-30 diastereomer, shown in Figure 9). The transition
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structure found for the (2+1) addition, TS3 (ΔG‡ = +24.8
rel
kcal/mol), is largely asynchronous and displays a bonding in-
teraction between the lone pair of the phosphorus and the
*(N=O) orbital of the nitrosoarene (Figure 10, P−O = 2.01
Å).33
Figure 7. DFT mechanism (M06-2X/6-311++G(d,p)/PCM) for de-
oxygenation of 2-nitrobiphenyl 1 by phosphetane 3. Relative free
energies (kcal/mol) in italics. Phosphorus (orange), oxygen (red),
nitrogen (blue), carbon (gray), hydrogen (white).
Figure 9. DFT mechanism (M06-2X/6-311++G(d,p)/PCM) for de-
oxygenation of 2-nitrosobiphenyl 28 by phosphetane 3. Relative
free energies (kcal/mol) shown in italics. Phosphorus (orange), ox-
ygen (red), nitrogen (blue), carbon (gray), hydrogen (white).
Figure
8.
DFT
transition
structures
(M06-2X/6-
311++G(d,p)/PCM) along the stepwise deoxygenation pathway
with selected bond metrics. Phosphorus (orange), oxygen (red), ni-
trogen (blue), carbon (gray), hydrogen (white).
The calculated (3+1) pathway is adequate to account for the ob-
served linear free energy correlation (see Sect. 2.3.3). DFT en-
ergy barriers computed for the (3+1) cheletropic addition of 5-
substituted 2-nitrobiphenyls with 3 (Table 5) reproduce with
good quantitative agreement the trend observed experimentally
in Figure 4; namely, that electron-withdrawing substituents ac-
celerate the rate of formal (3+1) cheletropic addition.
Table 5. Experimental and computational linear free energy re-
lationship correlation.
-X
σpara
kX/kH
expta
0.04
0.37
1.00
2.01
ΔΔG‡c
expta
calcb
+2.8
+0.5
0.0
-NMe2 –0.83
+1.9
+0.6
0.0
Figure
10.
DFT
transition
structures
(M06-2X/6-
311++G(d,p)/PCM) along the stepwise deoxygenation pathway
with selected bond metrics. Phosphorus (orange), oxygen (red), ni-
trogen (blue), carbon (gray), hydrogen (white).
-OMe
-H
–0.27
0
-Cl
0.23
–0.4
–1.9
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Efforts to locate transition structures associated with the col- providing an affirmative benchmark for this DFT pathway. The
1
2
3
4
5
6
7
8
lapse of oxazaphosphirane anti-30 led to TS4a and TS4b,
which describe two extremes in the bond forming sequence to-
ward the generation of carbazole (2) (Figure 10). Whereas TS4a
represents the dissociative pathway in which phosphetane P-ox-
ide 3•[O] departs before the C−N bond is formed to generate
biphenylnitrene 31, TS4b corresponds to the associative path-
way where C−N bond formation is fairly advanced before the
departure of 3•[O]. Estimation of the activation energies of
TS4a and TS4b using the Yamaguchi spin projection method
to account for spin contamination suggests that the dissociative
pathway denoted by TS4a (ΔG‡rel = +11.9 kcal/mol) is strongly
proposed (3+1)-pathway has not typically been invoked in Ca-
dogan chemistry (where proposals of acyclic zwitterionic inter-
mediates have prevailed9,13b); the data presented here provide
evidence, albeit indirect, for the intervention of such an ephem-
eral four-membered ring intermediate in phosphine/nitroarene
reactions. The second deoxygenation step again involves an all-
heteroatom cyclic intermediate, but spectroscopic identification
is permitted in this case. Heteronuclear NMR spectroscopy, bol-
stered by GIAO-DFT modeling, provide evidence for the for-
mation of an oxazaphosphirane upon low temperature mixing
of phosphetane 3 and 2-nitrosobiphenyl. Both Cadogan40 and
Sundberg26 have speculated on the involvement of an oxaza-
phosphirane species in the reaction pathway leading to product,
but such a species has not been directly observed. We believe
that our spectra represent the first characterization of the unu-
sual all-heteroatom (ONP) small-ring system. It seems likely
that thermal decomposition of this oxazaphosphirane interme-
diate above ca. –50 °C leads to dissociation of phosphetane
3•[O] with conversion of biarylnitrene residue to carbazole. Via
this pathway, the system here converges with the extensive
body of experimental and theoretical literature concerning the
electronic configuration and ring-closing reactivity of 2-bi-
phenylnitrene.35
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favored compared to the associative pathway via TS4b (ΔG‡
rel
= +43.1 kcal/mol). The incipient formation of the C−N bond in
TS4b affords a highly ordered transition structure that, relative
to intermediate anti-30, displays significant elongation of the
P−N bond distance.34 Taking into account that the combined
dissociation products (singlet biphenylnitrene 31 and 3•[O]) are
computed to be ΔGrel = +2.2 kcal/mol above the reactants and
that the calculated activation energy reported for its cyclization
via TS5 is ΔG‡rel = +6.9 kcal/mol,35,36 the computations are con-
sistent with the experimental detection of intermediates 30 and
the non-limiting barrier measured for their collapse to afford
carbazole (2).
The sequence of elementary steps proposed for nitroarene dou-
ble deoxygenation is usefully contextualized by isolobal anal-
ogy to the reactions of tricoordinate phosphorus compounds
with ozone and singlet oxygen (Figure 11). It is well-known that
phosphines and phosphites undergo formal (3+1) addition of O3
to form cyclic ozonides (R3P•O3) with pentacoordinated phos-
phorus centers contained within a four-membered trioxaphos-
phetane (i.e. O3P) ring system,41 which in view of the significant
thermodynamic driving force for adduct formation occur with
near diffusion-controlled rates. Subsequent thermal decomposi-
tion of the phosphine(-ite) ozonides I eliminates one equivalent
3. DISCUSSION
The synthetic method described above represents a robust and
process scalable organocatalytic approach to the synthesis of
carbazoles and indoles from appropriately decorated nitroarene
substrates. In view of the operational simplicity and compara-
tively mild conditions of the catalytic reaction protocol, it might
be expected that this approach could supplant traditional stoi-
chiometric Cadogan cyclization in circumstances where it is
currently employed.
of phosphine oxide and gives O2.41, In the case of the pro-
posed (3+1) addition of nitroarenes to phosphines, the thermo-
dynamic driving force for cheletropic addition is greatly dimin-
ished as compared to the O3 analogue; the kinetic barrier to ad-
duct formation is consequently increased to the extent that it
becomes kinetically limiting to catalysis. The azadioxophos-
phetane adducts III are therefore not observable and instead
proceed to fragment in retro-(2+2) fashion with elimination of
an equivalent of phosphine oxide and formation of a nitro-
soarene byproduct.
1
42
With respect to the function of the phosphorus-based catalyst,
the results of both synthetic and spectral investigations are con-
sistent with the requirement for interconversion of 3 and 3•[O]
during the course of the catalysis via PIII/PV=O redox cycling. It
has long been held that the central impediment to catalysis in
the PIII/PV=O couple stems from the kinetic and thermodynamic
inertness of phosphine oxide P=O bond. Despite these notions,
we find in the case of this catalytic Cadogan system that in situ
reduction of the phosphine oxide is not turnover limiting. In-
stead, the small ring phosphacycle in 3•[O] exhibits a high rate
of P=O deoxygenation by hydrosilane reductant to the tricoor-
dinate phosphetane 3, which represents the resting state of the
catalytic cycle. The rapid rate with which 3•[O] is deoxygenated
falls in line with precedent regarding the swift deoxygenation
of cyclic phosphine oxides,20b,20d, and builds on fundamental
37
notions of enhanced electrophilic reactivity of constrained
phosphacycles.38
The phosphorus-based catalyst operates on the nitro substrate to
effect double deoxygenation in a stepwise fashion. The first de-
oxygenation step is gated kinetically by a pericyclic (3+1)
cheletropic addition, which can be understood with the nitro
substrate expressing orbital character as a 4πs component39 and
the phosphetane as a 2ωs component.17b,18 Both the experimental
and computed Hammett correlations are in good agreement,
Figure 11. Isolobal correspondence between (A) O3 and (B) RNO2
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in their sequence of reactions with tricoordinate phosphorus com-
pounds.
TLC indicated the completion of the reaction. Following com-
pletion, the sample was allowed to cool and 10 mL of 3-6 M
HCl was added. The organic layer was separated and the aque-
ous layer was extracted with ethyl acetate (2x25 mL). The com-
bined organic layer was then dried over anhydrous sodium sul-
fate and concentrated in vacuo. Column chromatography on sil-
ica subsequently afforded the desired indole products.
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2
3
4
5
6
7
8
Continuing the isolobal analogy, singlet oxygen has been
shown to react with tricoordinate phosphorus to give adducts
that have been spectroscopically characterized by Selke at low
temperature as pentacoordinate dioxaphosphiranes (R3P•O2,
II).43 These R3PO2 compounds behave as electrophilic oxene
donors with loss of R3PO, in much the same way that the pro-
posed oxazaphosphirane IV (viz. 30) exhibits nitrene-like abil-
ity to aminate proximal Csp2-H bonds. The extent to which the
deoxygenation of nitro compounds by small-ring phosphacy-
cles via the proposed oxazaphosphirane serves as a general or-
ganophosphorus-catalyzed entry into nitrene- or nitrenoid-reac-
tivity is a matter of ongoing study.
5.3 Kinetics Experiments. For a kinetic run corresponding to
a single rate constant, a solution of 2-nitrobiphenyl (1) and
phosphetane P-oxide 3•[O] in n-butyl acetate was prepared un-
der nitrogen in an oven-dried, three-neck round-bottom flask
fitted with a silicon-tipped IR probe and a magnetic stir bar. The
solution temperature was stabilized at 108 + 2 °C and the reac-
tion was initiated by adding phenylsilane. Reaction monitoring
started 15 min after the addition of phenylsilane to ensure full
reduction of 3•[O] as determined by disappearance of the P-ox-
ide IR absorbance at 1195 cm-1. Sample aliquots (20 L + 10%)
were periodically taken using a calibrated automated sampler,44
diluted at room temperature into n-butyl acetate (80x) and ana-
lyzed using an HPLC system equipped with a C18 column (4.6
× 50 mm) and a SPD-20A/20AV UV−vis detector. Good
pseudo-first-order plots were obtained by monitoring the
growth of carbazole (2) relative to a standard calibration curve
and the initial rates (∆[1]/∆t) were calculated by multiplying the
pseudo-first-order reaction rate constants (exponential slopes)
by the corresponding concentrations of 2-nitrobiphenyl (1).
Rates were shown to be reproducible within experimental error
(+ 10%).
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4. CONCLUSION
We have demonstrated a catalytic Cadogan synthesis of useful
carbazole and indole products with a small-ring phosphacycle
catalyst and hydrosilane terminal reductant. Experimental and
computational modeling results implicate the operation of a
PIII/PV=O redox cycle in which phosphine 3 is the resting state
and initial deoxygenation of the nitro substrate represents the
turnover-limiting step. 31P NMR spectral monitoring and mod-
eling of the second deoxygenation event imply the intervention
of a spirocyclic pentacoordinate phosphorus intermediate ex-
hibiting an unprecedented oxazaphosphirane ring system, the
decomposition of which leads to carbazole product with loss of
phosphetane P-oxide through a nitrenoid pathway. Additional
studies on the structure and reactivity of pentacoordinate oxa-
zaphosphirane species of this type are warranted. Finally, the
mechanistic hypotheses advanced in this study provide a frame-
work for future biphilic organophosphorus catalyst design and
for reaction development within this PIII/PV=O manifold, both
of which constitute active ongoing research aims in our labora-
tories.
5.4 Computational Methods. Geometries were optimized in
Gaussian 0945 using the M06-2X46 density functional with the
6-311++G(d,p) basis set. The calculated energies (ΔG, 298.15
K, 1.0 atm) result from the sum of electronic and thermal free
energies as obtained from the frequency analysis at the same
level of theory. Frequency calculations for all stationary points
were carried out to describe them either as minima (i = 0) or as
first-order transition states (i = 1). For all transition structures,
visualization of the imaginary frequencies corresponded to the
expected normal mode for the elementary step under investiga-
tion. Intrinsic reaction coordinate calculations (IRC) were per-
formed from the transition states in forward and reverse direc-
tions to confirm the lowest energy reaction pathways that con-
nect the corresponding minima. See Supporting Information for
further details.
5. EXPERIMENTAL SECTION
A full description of the general experimental methods can be
found in the Supporting Information.
5.1 Representative Synthetic Procedure for Carbazoles. To
a 40 mL screw-cap vial fitted with a stir bar was added 1 gram
of o-nitrobiphenyl substrate, 20 mol% of phosphetane oxide
precatalyst 3•[O], n-butyl acetate (1 M), and phenylsilane (2
equiv). A cap was screwed on and the reaction was heated at
120 °C with stirring until TLC indicated the completion of re-
action. Following cyclization, the homogeneous reaction mix-
ture was cooled to room temperature, during which time a pre-
cipitate was formed. The solids were collected on a glass frit
and washed with one portion of CH2Cl2 to yield the carbazole
products with >98% purity by HPLC analysis.
ASSOCIATED CONTENT
Supporting Information
1
Synthetic procedures; H, 13C, 15N and 31P NMR spectra; kinetics
data; computational details and Cartesian coordinates
AUTHOR INFORMATION
Corresponding Authors
*michael.luzung@bms.com
*radosevich@mit.edu
5.2 Representative Synthetic Procedure for Indoles. To a
flame-dried 25 mL round-bottom flask fitted with a stir bar was
added 1 gram of o-nitrostyrene substrate, 20 mol% of phos-
phetane oxide precatalyst 3•[O], and a septum. Following evac-
uation and the introduction of nitrogen on a Schlenk line, dry n-
butyl acetate (1 M) was added via syringe from a SureSeal bot-
tle. Phenylsilane (2 equiv) was added lastly and heating/stirring
(120 °C, ~500 rpm) was continued under positive nitrogen until
Notes
The authors declare no competing financial interests.
ACKNOWLEDGMENT
Financial support was provided by NIH NIGMS (GM114547),
MIT, and Bristol-Myers Squibb. We thank the Buchwald labora-
tory (MIT) for access to equipment and chemicals.
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