A Biphilic Phosphetane Catalyzes N-N Bond-Forming Cadogan Heterocyclization via PIII/PV = O Redox Cycling

Article abstract of DOI:10.1021/jacs.7b03260

A small-ring phosphacycle, 1,2,2,3,4,4-hexamethylphosphetane, is found to catalyze deoxygenative N-N bond-forming Cadogan heterocyclization of o-nitrobenzaldimines, o-nitroazobenzenes, and related substrates in the presence of hydrosilane terminal reductant. The reaction provides a chemoselective catalytic synthesis of 2H-indazoles, 2H-benzotriazoles, and related fused heterocyclic systems with good functional group compatibility. On the basis of both stoichiometric and catalytic mechanistic experiments, the reaction is proposed to proceed via catalytic P^III/P^V = O cycling, where DFT modeling suggests a turnover-limiting (3+1) cheletropic addition between the phosphetane catalyst and nitroarene substrate. Strain/distortion analysis of the (3+1) transition structure highlights the controlling role of frontier orbital effects underpinning the catalytic performance of the phosphetane.

Full text of DOI:10.1021/jacs.7b03260

Communication
pubs.acs.org/JACS
A Biphilic Phosphetane Catalyzes N−N Bond-Forming Cadogan
Heterocyclization via PIII/PVO Redox Cycling
Trevor V. Nykaza,† Tyler S. Harrison,† Avipsa Ghosh,† Rachel A. Putnik,‡
and Alexander T. Radosevich*,†
†Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, United States
‡Department of Chemistry, The Pennsylvania State University, University Park, Pennsylvania 16802, United States
S
* Supporting Information
temperatures; the standard Cadogan protocol calls for reaction
ABSTRACT: A small-ring phosphacycle, 1,2,2,3,4,4-hexa-
methylphosphetane, is found to catalyze deoxygenative
N−N bond-forming Cadogan heterocyclization of o-
nitrobenzaldimines, o-nitroazobenzenes, and related sub-
strates in the presence of hydrosilane terminal reductant.
The reaction provides a chemoselective catalytic synthesis
of 2H-indazoles, 2H-benzotriazoles, and related fused
heterocyclic systems with good functional group compat-
ibility. On the basis of both stoichiometric and catalytic
mechanistic experiments, the reaction is proposed to
proceed via catalytic PIII/PVO cycling, where DFT
modeling suggests a turnover-limiting (3+1) cheletropic
addition between the phosphetane catalyst and nitroarene
substrate. Strain/distortion analysis of the (3+1) transition
structure highlights the controlling role of frontier orbital
effects underpinning the catalytic performance of the
phosphetane.
in neat refluxing triethylphosphite (bp 156 °C), although milder
conditions have been reported in some cases.15 We questioned
whether inherently nontrigonal biphilic phosphines, which
colocalize donor and acceptor behavior at P, might facilitate O-
atom transfer from the nitro substrate under milder conditions
and in a manner conducive to PIII/PVO redox cycling (Figure
1).
Figure 1. Phosphine biphilicity and N−N bond-forming Cadogan
heterocyclization via PIII/PVO-catalyzed reductive O-atom transfer.
Starting from our reported conditions for deoxygenative
carbonyl functionalization as a point of departure, treatment of 1
with substoichiometric quantities of aminophosphetane P-oxide
3·[O] (15 mol%) and phenylsilane (2 equiv) in PhMe at 100 °C
was indeed found to afford indazole 2, albeit in modest yield
(Table 1, entry 1). Further optimization studies converged on
the simple 1,2,2,3,4,4-hexamethylphosphetane P-oxide 5·[O] as
the optimal catalyst for this transformation (see SI for details); in
the event, phosphetane P-oxide 5·[O] is found to catalyze
deoxygenative heterocyclization, delivering product 2 in 83% GC
yield within 3 h at 100 °C (entry 3). Neither phospholane-based
(6·[O] and 7·[O], entries 4 and 5) nor acyclic (8·[O], entry 6)
phosphorus precatalysts exhibit similar catalytic reactivity under
otherwise identical conditions. Control experiments (entries 7
and 8) confirm that no reaction is observed in the absence of
either 5·[O] or terminal reductant PhSiH3; the transformation is
demonstrably under catalyst control. Consistent with the notion
of PIII/PVO redox cycling, the use of tricoordinate (σ3-P)
precatalyst 1,2,2,3,4,4-hexamethylphosphetane 5 affords inda-
zole 2 with qualitatively similar results as 5·[O] (entry 9). That
said, the ease with which phosphine oxide 5·[O]an air-stable
solidis both handled on laboratory scale and reduced in situ to
516 recommended its use as precatalyst in subsequent studies.
ricoordinate phosphorus reagents are versatile O-atom
T
acceptors,1 and the conversion PIII→PVO drives
numerous valuable synthetic transformations.2−4 Despite great
utility, the inefficient generation of stoichiometric phosphine
oxide waste inherent to these methods is regarded as a key
limitation. In recent years, though, several new catalytic methods
involving cycling through phosphine oxide intermediates have
emerged,5 in both redox-neutral6,7 and redox-driven modes.8−10
As part of a program aimed at developing designer main-group
compounds as broadly useful biphilic11 catalysts in organic
synthesis,12 we recently reported the use of phosphetanes as O-
atom-transfer catalysts operating via PIII/PVO redox cy-
cling.12c In this Communication, we advance this biphilic
catalysis concept by describing a catalytic N−N bond-forming
heterocyclization enabled by phosphetane-catalyzed reductive
O-atom transfer. Beyond broadening the repertoire of phosphine
oxide redox-catalyzed organic transformations, this study
documents a dominant electronic basis for the superior
performance of phosphetane catalysts that provides a framework
for future targeted design of geometrically deformed main-group
compounds as biphilic catalysts.
Cadogan13 and Sundberg14 have shown that phosphine-
mediated exhaustive deoxygenation of o-functionalized nitro-
benzene derivatives drives phenylnitrene-like azacyclizations.
Most commonly, these transformations employ superstoichio-
metric amounts of phosphorus-based reagents at elevated
Received: March 31, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/jacs.7b03260
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
a
Table 1. Phosphacycles as Catalysts for Deoxygenative
Heterocyclization of o-Nitrobenzaldimine 1
Table 2. Examples of Catalytic Cadogan Synthesis
a
entry
R3PO
silane
conversion (%)
yield (%)
1
2
3
4
5
6
7
8
9
3·[O]
4·[O]
5·[O]
6·[O]
7·[O]
8·[O]
none
5·[O]
5
PhSiH3
PhSiH3
PhSiH3
PhSiH3
PhSiH3
PhSiH3
PhSiH3
none
49
45
99
21
96
21
14
12
99
20
31
83
1
24
6
0
0
PhSiH3
93
a
Conversion and yield determined via GC vs internal standard.
The results of our studies into the scope of this catalytic
transformation are collected in Table 2. With respect to N-
substitution, aliphatic substituents (Table 2A) are well tolerated,
including 1° (9), 2° (10), and 3° (11) moieties, and basic
nitrogen functionality may be incorporated without incident
(compare 12 and 13). Likewise, aromatic substrates of diverse
substitution (Table 2B) are suitable substrates; halogenated
(17−19), electron-rich (20, 21), electron-poor (23, 25),
unsaturated (24), and sterically demanding (26) N-aryl-
substituted substrates all undergo smooth catalytic indazole
formation. Polyheterocyclic products (30, 31) may be similarly
prepared. Free hydroxyl moieties do not inhibit deoxygenative
heterocyclization (22, 32), although such substrates may
undergo in situ silylation by the PhSiH3 reductant; desilylative
workup ensures recovery of the free OH group. Challenging
substrates for the current method include, unsurprisingly, those
with multiple nitro moieties (Table 2C, 33); evidently the
catalyst does not selectively recognize the o-imino nitro moiety.
However, a range of other reducible functionalities, including
nitriles (23), amides (29), and esters (36), are all carried through
the deoxygenative cyclization reaction without incident.
The reaction is similarly amenable to non-benzaldimine
substrates, permitting the synthesis of diverse heterocyclic
structures through catalytic N−N bond formation (Table
2D,E). For instance, deoxygenative heterocyclization of 2-(2-
pyridyl)nitrobenzene delivers the fused polyheterocyclic pyrido-
[1,2-b]indazole (39) in near quantitative yield under standard
catalytic conditions within 4 h. Relatedly, indazolodihydroimid-
azoles (40), -tetrahydropyrimidines (41), and -dihydrooxazoles
(42) are accessible under standard conditions. Stereochemistry
adjacent to the reaction centers is retained upon cyclization (42).
Beyond indazole synthesis, the preparation of N-aryl-2H-
benzotriazoles (43-45) is achieved by deoxygenative hetero-
cyclization of the corresponding substituted o-nitroazobenzene.
In situ spectral monitoring of catalytic reactions provides
information regarding both the mechanistic course of the
transformation and speciation of active phosphorus compounds
a
b
Yields reported for isolated products. Treatment with TBAF prior to
c
silica gel chromatography. Single stereoisomer by HPLC.
°C) of a standard catalytic transformation (1 equiv of 1, 15 mol%
of 5·[O], 2 equiv of PhSiH3, 1 M in C7D8) show the appearance
of product indazole 2 over the course of ca. 1.5 h at the expense of
starting imine substrate 1; no long-lived intermediates are
1
during catalysis. H NMR spectra (400 MHz, toluene-d8, 100
B
DOI: 10.1021/jacs.7b03260
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
observed by 1H NMR spectroscopy. Under identical conditions,
31P NMR spectra show the rapid conversion of 5·[O] (δ 53.2
ppm) to an epimeric mixture of the corresponding phosphetane
5 (δ 32.4 ppm (major, anti); δ 18.9 ppm (minor, syn)), which
persists in solution until the reaction is complete (see SI). From
these data, we infer that 5 represents the catalytic resting state,
with the initial deoxygenation of substrate 1 as the turnover-
limiting step.17 Regrettably, direct kinetic observation of reaction
steps following initial deoxygenation is therefore precluded;
presumably, though, the nitroso derivative formed by deoxyge-
nation of 1 is an obligate intermediate that proceeds on to
observed product in a series of fast following steps.18
Under stoichiometric pseudo-first-order conditions with
excess phosphine reagent, we find that consumption of substrate
1 is markedly faster with phosphetane 5 than with nBu3P 8 (krel ≈
8, see SI Figure S2); phosphetane 5 is evidently superior to
acyclic 8 for Cadogan cyclization. In an effort to understand the
origin of this rate difference, we undertook DFT modeling
studies (Figure 2). Direct O-atom transfer from nitromethane to
Figure 3. Transition structures and distortion/interaction analyses for
(3+1) transition states (M06-2X/6-311++g(d,p)): (A) phosphetane
5
8
TS2 ′ and (B) Me3P TS2 ′. Phosphine distortion energy (ΔEdP⧧) in
green, nitromethane distortion energy (ΔEdN⧧) in blue, fragment
interaction energy (ΔEi⧧) in red, activation energy (ΔE⧧) in black. All
energies in kcal/mol without zero-point correction.
than Me3P 8′ (−9.7 kcal/mol). The inference from this analysis
is that the differential performance of the small-ring phosphetane
and trimethylphosphineboth of which compositionally are
simple trialkylphosphinesis driven primarily by electronic
(orbital) as opposed to enthalpic (ring strain) effects.
The difference in interaction energies for the (3+1) addition
transition structures can be rationalized by frontier orbital
inspection. Figure 4 depicts the Kohn−Sham HOMO and
Figure 2. DFT mechanisms of nitro deoxygenation (M06-2X/6-311+
+g(d,p)). Relative electronic energies in kcal/mol with unscaled zero-
point correction.
5
8
phosphetane 5′ and trimethylphosphine 8′ (via TS1 ′ and TS1 ′,
respectively) is found to be high in energy. Instead, a stepwise
mechanism proceeding through pentacoordinate azadioxaphos-
phetanes I5′ and I8′ is found at lower energies. The rate-
Figure 4. Frontier Kohn−Sham orbital plots and orbital energies for
reactant fragments deformed to transition-state structures (M06-2X/6-
31g(d)).
5
controlling transition structure along this pathway (i.e., TS2 ′
and TS2 ′) involves a (3+1) cheletropic addition19,20 of MeNO2
8
to 5′ and 8′, respectively. Subsequent decomposition of I5′ and
5
8
I8′ via retro-(2+2) fragmentation (TS2 ′ and TS2 ′) then follows
with a low barrier. This (3+1)/retro-(2+2) pathway is
mechanistically analogous and orbitally equivalent to known
reactivity of phosphines(-ites) with O3.20
LUMO of each reactant distorted to the transition-state
structure. Whereas both phosphetane and trimethylphosphine
exhibit HOMOs (nonbonding lone pair) of nearly identical
energy (−6.95 eV), LUMO(5′) resides ca. 0.8 eV lower in energy
than LUMO(8′). In effect, the geometric constraint enforced by
the four-membered ring of the phosphetane 5′ results in a
marked lowering of the LUMO that preferentially permits
synergistic interactions of HOMO(5′)→LUMO(MeNO2) and
To understand further the superiority of the phosphetane with
5
respect to deoxygenation, the (3+1) transition structures TS2 ′
8
and TS2 ′ were analyzed within the distortion/interaction
model21 (Figure 3). Despite the presence of the small ring in
⧧
5′, the destabilizing distortion energy (ΔEd ) within transition
structures TS2 ′ and TS2 ′ is nearly identical (39.2 vs 38.8 kcal/
mol, respectively), being driven to an overwhelming extent by
pyramidalization of the nitro substrate, not by geometric
reorganization about phosphorus. By consequence, the lower
HOMO(MeNO2)→LUMO(5′) in a [π4s + 2s] fashion.22 We
5
8
ω
note that the low frontier orbital energy gap of phosphetanes has
previously been invoked by Chesnut and Quin to rationalize
nonmonotonic chemical shift anisotropy trends in phospha-
cycloalkanes.23 Relatedly, Hudson24 and Westheimer25 have
noted the extent to which ring constraint increases electrophilic
5
overall energy of TS2 ′ arises from a significantly larger stabilizing
interaction energy (ΔEi⧧) for phosphetane 5′ (−17.5 kcal/mol)
C
DOI: 10.1021/jacs.7b03260
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
February 2, 2012. (c) O’Brien, C. J.; Lavigne, F.; Coyle, E. E.; Holohan,
A. J.; Doonan, B. J. Chem. - Eur. J. 2013, 19, 5854. (d) O’Brien, C. J.;
Nixon, Z. S.; Holohan, A. J.; Kunkel, S. R.; Tellez, J. L.; Doonan, B. J.;
Coyle, E. E.; Lavigne, F.; Kang, L. J.; Przeworski, K. C. Chem. - Eur. J.
2013, 19, 15281. (e) Coyle, E. E.; Doonan, B. J.; Holohan, A. J.; Walsh,
K. A.; Lavigne, F.; Krenske, E. H.; O’Brien, C. J. Angew. Chem., Int. Ed.
2014, 53, 12907.
(9) (a) van Kalkeren, H. A.; Leenders, S. H. A. M.; Hommersom, C. R.
A.; Rutjes, F. P. J. T.; van Delft, F. L. Chem. - Eur. J. 2011, 17, 11290.
(b) van Kalkeren, H. A.; Bruins, J. J.; Rutjes, F. P. J. T.; van Delft, F. L.
Adv. Synth. Catal. 2012, 354, 1417. (c) Lenstra, D. C.; Rutjes, F. P. J. T.;
character at phosphorus. The importance of orbital effects in
reactions of strained ring systems has been noted by Hoz.26
In summary, we have found that a readily accessible27
phosphetane is a suitable catalyst for the Cadogan indazole
synthesis. The method provides a simple phosphacatalytic
approach to a valuable N−N bond-forming mode that has
previously been accomplished via (super)stoichiometric reagent
chemistry,13,28 transition-metal catalysis,29 or alternative high-
energy azide substrates.30 Whereas previous studies involving
PIII/PVO redox cycling have focused primarily on ring strain
arguments underpinning catalytic turnover of phosphine oxides
by silane reductants, the results above suggest a dominant
electronic component to the overall biphilic function of the
phosphetane catalyst. Work continues in an effort to establish
further the biphilic reactivity of phosphetanes as generalized
platforms for catalytic reductive O-atom transfer.
́
Mecinovic, J. Chem. Commun. 2014, 50, 5763.
(10) (a) Harris, J. R.; Haynes, M. T.; Thomas, A. M.; Woerpel, K. A. J.
Org. Chem. 2010, 75, 5083. (b) Kosal, A. D.; Wilson, E. E.; Ashfeld, B. L.
Angew. Chem., Int. Ed. 2012, 51, 12036. (c) Fourmy, K.; Voituriez, A.
Org. Lett. 2015, 17, 1537. (d) Werner, T.; Hoffmann, M.; Deshmukh, S.
Eur. J. Org. Chem. 2015, 2015, 3286.
(11) Kirby, A. J.; Warren, S. G. The Organic Chemistry of Phosphorus;
Elsevier: Amsterdam, 1967; p 20.
(12) (a) Dunn, N. L.; Ha, M.; Radosevich, A. T. J. Am. Chem. Soc. 2012,
134, 11330. (b) Reichl, K. D.; Dunn, N. L.; Fastuca, N. J.; Radosevich, A.
T. J. Am. Chem. Soc. 2015, 137, 5292. (c) Zhao, W.; Yan, P. K.;
Radosevich, A. T. J. Am. Chem. Soc. 2015, 137, 616.
(13) (a) Cadogan, J. I. G.; Cameron-Wood, M.; Mackie, R. K.; Searle,
R. J. G. J. Chem. Soc. 1965, 4831. (b) Cadogan, J. I. G. Synthesis 1969,
1969, 11. (c) Cadogan, J. I. G.; Todd, M. J. J. Chem. Soc. C 1969, 2808.
(14) Sundberg, R. J. J. Org. Chem. 1965, 30, 3604.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/jacs.7b03260.
■
S
Synthetic procedures; 1H, 13C, 19F, and 31P NMR spectra;
computational details; and Cartesian coordinates (PDF)
(15) Genung, N. E.; Wei, L.; Aspnes, G. E. Org. Lett. 2014, 16, 3114.
(16) (a) Marsi, K. L. J. Am. Chem. Soc. 1969, 91, 4724. (b) Marsi, K. L. J.
Org. Chem. 1974, 39, 265.
(17) A catalytic mechanism proceeding via initial imine reduction is
excluded by the observation that reaction of N-(2-nitrobenzyl)aniline
under standard catalytic conditions gives an incomparably low yield of
indazole 2. See SI for details.
(18) For theoretical studies and discussion of related downstream
events, see: Davies, I. W.; Guner, V. A.; Houk, K. N. Org. Lett. 2004, 6,
743.
AUTHOR INFORMATION
Corresponding Author
*radosevich@mit.edu
ORCID
Avipsa Ghosh: 0000-0003-3786-0453
Alexander T. Radosevich: 0000-0002-5373-7343
Notes
■
The authors declare no competing financial interest.
(19) (3+1) additions are rare, but precedented: (a) Xiong, Y.; Yao, S.;
Driess, M. Organometallics 2010, 29, 987. (b) May, A.; Roesky, H. W.;
Herbst-Irmer, R.; Freitag, S.; Sheldrick, G. M. Organometallics 1992, 11,
15.
(20) (a) Thompson, Q. E. J. Am. Chem. Soc. 1961, 83, 845.
(b) Stephenson, L. M.; McClure, D. E. J. Am. Chem. Soc. 1973, 95, 3074.
(21) (a) Ess, D. H.; Houk, K. N. J. Am. Chem. Soc. 2007, 129, 10646.
(b) Fernandez, I.; Bickelhaupt, F. M. Chem. Soc. Rev. 2014, 43, 4953.
́
(22) We have previously reported on the phosphapericyclic reactivity
of phosphetanes as ω2s-components; see ref 12b.
ACKNOWLEDGMENTS
■
Dedicated to Prof. Steven M. Weinreb on the occasion of his
75th birthday. This research was supported by NIH NIGMS
under award no. GM114547. A.T.R. gratefully acknowledges
additional support from the Alfred P. Sloan Foundation and
Amgen. We thank the Buchwald laboratory (MIT) for access to
equipment and chemicals.
(23) Chesnut, D. B.; Quin, L. D.; Wild, S. B. Heteroat. Chem. 1997, 8,
451.
REFERENCES
■
(1) Rowley, A. G. In Organophosphorus Reagents in Organic Synthesis;
Cadogan, J. I. G., Ed.; Academic Press: London, 1979; pp 295.
(2) Maryanoff, B. E.; Reitz, A. B. Chem. Rev. 1989, 89, 863.
(3) Swamy, K. C. K.; Kumar, N. N. B.; Balaraman, E.; Kumar, K. V. P. P.
Chem. Rev. 2009, 109, 2551.
(24) Hudson, R. F.; Brown, C. Acc. Chem. Res. 1972, 5, 204.
(25) Westheimer, F. H. Acc. Chem. Res. 1968, 1, 70.
(26) Sella, A.; Basch, H.; Hoz, S. J. Am. Chem. Soc. 1996, 118, 416.
(27) (a) McBride, J. J.; Jungermann, E.; Killheffer, J. V.; Clutter, R. J. J.
Org. Chem. 1962, 27, 1833. (b) Marinetti, A.; Carmichael, D. Chem. Rev.
2002, 102, 201.
(4) Appel, R. Angew. Chem., Int. Ed. Engl. 1975, 14, 801.
(5) (a) Marsden, S. P. In Sustainable Catalysis; Dunn, P. J., Hii, K. K.,
Krische, M. J., Williams, M. T., Eds.; John Wiley & Sons, Inc.: New York,
2013; pp 339−361. (b) van Kalkeren, H. A.; van Delft, F. L.; Rutjes, F. P.
J. T. ChemSusChem 2013, 6, 1615. (c) An, J.; Denton, R. M.; Lambert, T.
H.; Nacsa, E. D. Org. Biomol. Chem. 2014, 12, 2993. (d) Voituriez, A.;
Saleh, N. Tetrahedron Lett. 2016, 57, 4443.
(28) Sun, F.; Feng, X.; Zhao, X.; Huang, Z.-B.; Shi, D.-Q. Tetrahedron
2012, 68, 3851.
(29) (a) Akazome, M.; Kondo, T.; Watanabe, Y. J. Chem. Soc., Chem.
Commun. 1991, 1466. (b) Akazome, M.; Kondo, T.; Watanabe, Y. J. Org.
Chem. 1994, 59, 3375. (c) Kumar, M. R.; Park, A.; Park, N.; Lee, S. Org.
Lett. 2011, 13, 3542. (d) Okuro, K.; Gurnham, J.; Alper, H. Tetrahedron
Lett. 2012, 53, 620. (e) Moustafa, A. H.; Malakar, C. C.; Aljaar, N.;
Merisor, E.; Conrad, J.; Beifuss, U. Synlett 2013, 24, 1573.
(30) (a) Stokes, B. J.; Vogel, C. V.; Urnezis, L. K.; Pan, M.; Driver, T. G.
Org. Lett. 2010, 12, 2884. (b) Hu, J.; Cheng, Y.; Yang, Y.; Rao, Y. Chem.
Commun. 2011, 47, 10133.
(6) Marsden, S. P.; McGonagle, A. E.; McKeever-Abbas, B. Org. Lett.
2008, 10, 2589.
(7) (a) Denton, R. M.; An, J.; Adeniran, B. Chem. Commun. 2010, 46,
3025. (b) Denton, R. M.; An, J.; Adeniran, B.; Blake, A. J.; Lewis, W.;
Poulton, A. M. J. Org. Chem. 2011, 76, 6749. (c) An, J.; Tang, X.; Moore,
J.; Lewis, W.; Denton, R. M. Tetrahedron 2013, 69, 8769.
(8) (a) O’Brien, C. J.; Tellez, J. L.; Nixon, Z. S.; Kang, L. J.; Carter, A.
L.; Kunkel, S. R.; Przeworski, K. C.; Chass, G. A. Angew. Chem., Int. Ed.
2009, 48, 6836. (b) O’Brien, C. J. U.S. Patent US20120029211 A1,
D
DOI: 10.1021/jacs.7b03260
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX