Catalytic formal [2+2+1] synthesis of pyrrolesfrom alkynes and diazenes via TiII/TiIV
redox catalysisZachary W. Gilbert, Ryan J. Hue and Ian A. Tonks*
Pyrroles are structurally important heterocycles. However, the synthesis of polysubstituted pyrroles is often challenging.Here, we report a multicomponent, Ti-catalysed formal [2+2+1] reaction of alkynes and diazenes for the oxidativesynthesis of penta- and trisubstituted pyrroles: a nitrenoid analogue to classical Pauson–Khand-type syntheses ofcyclopentenones. Given the scarcity of early transition-metal redox catalysis, preliminary mechanistic studies arepresented. Initial stoichiometric and kinetic studies indicate that the mechanism of this reaction proceeds through aformally TiII/TiIV redox catalytic cycle, in which an azatitanacyclobutene intermediate, resulting from [2+2] alkyne + Tiimido coupling, undergoes a second alkyne insertion followed by reductive elimination to yield pyrrole and a TiII species.The key component for catalytic turnover is the reoxidation of the TiII species to a TiIV imido via the disproportionation ofan η2-diazene-TiII complex.
The development of earth-abundant and nontoxic catalysts forprecision chemical transformations is an imperative endea-vour of modern synthesis, and recent years have seen a great
effort towards replacing the precious group 9 and 10 metal catalystswith their lighter base metal congeners1. Complementary to thisresearch, many synthetically practical processes that use earth-abun-dant early transition-metal or lanthanide catalysts have also beendeveloped2–12. However, due to the oxophilic, electropositivenature of early transition metals, the majority of organometallic cat-alytic processes that use them are redox-neutral4–6. Examples of cat-alytic processes that rely on early transition-metal redox processesare rare and mostly limited to C–C7–11 or C–H12 bond-forming reac-tions, the most notable class being Kulinkovich-type cyclopropana-tions8. Instead of proceeding through oxidative processes, earlytransition-metal-catalysed C–N bond-forming reactions typicallyoccur through redox-neutral alkene/alkyne hydroamination5 andrelated pathways6,7, and the only example of catalytic oxidativeC–N bond formation is a report from Heyduk that uses aZr complex with a redox non-innocent ligand to catalyticallycouple isonitriles and azides to form carbodiimides13.
Polysubstituted pyrroles play a key role in pharmaceuticals14,materials15, dyes16 and natural products17, and are often challengingsynthetic targets18–21. Various heterocycles have previously beenformed from early transition metallacycles, but these reactionsare predominantly limited to stoichiometric reactivity22–24. A cat-alytic [2+2+1] cyclization involving nitrenes25 and alkynes wouldbe closely related to the Pauson–Khand synthesis of cyclopente-nones, and adapting such well-established synthetic methods26 tonitrenes would allow for the rapid development of complex func-tionalized pyrroles27–29.
Two reports have previously demonstrated the stoichiometricoxidative formation of pyrroles from alkynes by Ti complexes(Fig. 1). First, Rothwell30 reported that bis(aryloxide)titanacyclo-pentadienes can insert benzo[c]cinnoline into a Ti–C bond to forma diazatitanacycloheptadiene, which on heating in the presence ofexcess benzo[c]cinnoline undergoes ring contraction to generate aTi imido and a tethered pyrrole. More recently, Bercaw31 reported
the sub-stoichiometric oxidative formation of pyrroles duringTi-catalysed alkyne hydroamination reactions, which were generatedvia reductive elimination of expanded metallacycles to yield TiII
species32,33. Based on this precedent, we were interested in closinga potential catalytic cycle by reoxidation of TiII to TiIV = NR witha nitrene oxidant34. Given several reports of low-valent Ti speciescleaving diazenes to imidos35–37, we were led to explore the reactivityof azobenzene, which may serve as a weakly nucleophilic nitrenesource and simple Ti imidos, (L)nTiCl2(NR) (L = HNMe2,py;n = 2, 3; R = Ph, Tol, tBu)38,39, with various alkynes.
Here, we report the (py)3TiCl2(NR)-catalysed synthesis of pyr-roles through a three-component formal [2+2+1] oxidative couplingof alkynes and diazenes (Fig. 1b). This methodology represents anew retrosynthetic disconnection in the catalytic synthesis ofpyrroles, and also demonstrates a unique example of a catalyticoxidative nitrene transfer by a TiII/TiIV redox couple.
Results and discussionReaction of 10 mol% 1a with 2 equiv. 3-hexyne (2a) and 0.5 equiv.azobenzene (3a) in mesitylene at 180 °C for 24 h yielded the cataly-tic production of N-phenyl-2,3,4,5-tetraethylpyrrole (4a) (22%), theformal [2+2+1] oxidative coupling product of two alkynes and 0.5azobenzenes (Fig. 2, equation (1)). Additionally, stoichiometricamounts (10%) of the hydroamination product, N-phenylhexan-3-imine, and small amounts of the cyclotrimerization product, hex-aethylbenzene, were observed. Although the yield and selectivity ofthis initial reaction are poor, three observations can be made. First,azobenzene is capable of turning over the catalytic reaction throughreoxidation of low-valent Ti intermediates. Second, the [2+2+1]reaction is competing with hydroamination, and the two reactioncycles probably share a common Ti intermediate. Third, TiII inter-mediates must be involved due to the presence of competitive alkynetrimerization10. In this case, hydroamination occurs via double pro-tonation of an azatitanacyclobutene intermediate by the 2 equiv.dimethylamine present in the Ti imido precatalyst.
By using an aprotic catalyst, (py)3TiCl2(NPh) (1b)39, quantitativeconversion to the desired [2+2+1] product was observed with
Department of Chemistry, University of Minnesota – Twin Cities, 207 Pleasant St SE, Minneapolis, Minnesota 55455, USA. *e-mail: [email protected]
ARTICLESPUBLISHED ONLINE: 2 NOVEMBER 2015 | DOI: 10.1038/NCHEM.2386
minimal competing cyclotrimerization and no hydroamination(Fig. 2, equation (2)). Interestingly, both NPh units in azobenzeneare incorporated into the product. When using 10 mol% (py)3TiCl2-(Ntol) (1c) or (py3)TiCl2(N
tBu) (1d), 10% of the product containstolyl- or tBu-functionalized pyrrole, indicating that reactivity occursthrough the imido functionality and that virtually all of the Ti catalystundergoes reaction.
The preliminary mechanism for the catalytic oxidative formal[2+2+1] cyclization of alkynes and diazenes is presented inFig. 3a. First, a TiIV imido (I) undergoes [2+2] addition with analkyne to form an azatitanacyclobutene (II), identical to thefirst step for Ti-catalysed hydroamination5,40–42. This step issupported by the initial catalytic experiments with 1a, wherehydroamination competed with [2+2+1] cyclization. Next, asecond equivalent of alkyne inserts into the azatitanacyclobuteneto form an azatitanacyclohexadiene (III). Second insertionsinto azatitanacycles are quite rare, but have previously beenobserved by Mountford32 (alkynes, stoichiometric) and Odom(isocyanides, catalytic)43.
After second insertion, reductive elimination from III yields thepyrrole product and a TiII intermediate (IV). The resulting TiII
intermediate can then either unproductively trimerize alkyne10, orbe trapped by azobenzene to form a TiII η2-azobenzene44–47,adduct V, which then disproportionates35–37 into a TiIV imido (I)to close the catalytic cycle. This reductive elimination may be facili-tated by the coordination of azobenzene or alkyne, either of whichcould act as a ‘redox-non-innocent’ ligand and immediately acceptthe electrons from reductive elimination to avoid a long-lived TiII
intermediate. Under either scenario, the binding competition ofazobenzene and alkyne determines whether alkyne trimerizationor productive reoxidation occurs.
The reoxidation of the transient TiII species to a TiIV imido isproposed to involve a disproportionation of an η2-azobenzenecomplex into a TiIV imido and 0.5 equiv. azobenzene. To examinethe stoichiometric viability of this rather unique catalytic reoxida-tion mechanism, a Ti η2-azobenzene complex, (HNMe2)2TiCl2(PhNNPh) (7), which is similar in structure to the proposedTiII η2-azobenzene adduct V, was synthesized via protonolysis ofTiCl2(NMe2)2 by 1,2-diphenylhydrazine (Fig. 4). The X-raystructure of 7 reveals an N–N bond length of 1.420(3) Å, indicat-ing a reduced η2-PhN-NPh(2−) hydrazido unit bound to a TiIV
centre instead of a TiII azobenzene adduct37,47. Thermolysis of 7in α,α,α-trifluorotoluene (TFT) results in rapid, full conversion tothe TiIV imido 1a (confirmed by 1H NMR), with concomitant
production of 0.5 equiv. azobenzene, consistent with the η2-azoben-zene adduct being a viable catalytic intermediate.
Complex 7 could disproportionate to 1a through two limiting path-ways: (1) by dimerization48 to generate a Ti2N4 species that could thenretrocyclize into 1a and free azobenzene (Fig. 3b, top pathway) or (2)by decoordination of azobenzene to make a free TiII species that couldthen comproportionate36 with another equivalent of 7 to generate2 equiv. 1a (Fig. 3b, bottom pathway). The disproportionation islikely to occur through the dimerization pathway, because additionof tolNNtol to 7 yields neither tolyl-functionalized Ti imido nortolNNPh crossover products upon heating and disproportionation.
Notably, later transition metals and complexes with redox-activeligands have been reported to perform the reverse reaction—coup-ling metal imidos to generate diazenes49–52. For this [2+2+1] coup-ling, the large thermodynamic preference for TiII oxidation drivesthe reaction to favour diazene cleavage to form imidos. The use ofdiazenes to promote Ti reoxidation is critical for catalysis. Other‘nitrene’ oxidants such as aryl azides or PhINTs do not yieldproductive reactivity.
Having determined the optimum reaction conditions (Supple-mentary Sections 1 and 2), the scope of the reaction was examinedusing a number of alkynes at 110 °C in TFT. The results of reactionswith internal and terminal alkynes, diynes and enynes are shown inTable 1. Overall, internal and terminal alkynes with alkyl, aryl andsilyl groups are well tolerated, but alkynyl esters, tethered alkylethers and bis(trimethylsilyl)acetylene do not react underoptimized conditions (see Supplementary Section 3).
Alkynes that are known to rapidly undergo cyclotrimerization(such as terminal alkynes) require excess azobenzene to give highyields. For example, phenylacetylene (2g) gave almost no pyrroleproducts (<5%) under standard conditions; instead, the major pro-ducts observed were 1,2,4-triphenylbenzene and 1,3,5-triphenylben-zene. Increased yields of the pyrrole regioisomers 5g and 6g can beobtained by using a sixfold excess of 3a to favour azobenzenebinding over phenylacetylene binding to the TiII intermediate IV.
Further evidence for the binding competition of alkyne and azo-benzene can be observed in the reactions of tethered diynes.Reaction of 2,7-nonadiyne (2k) with stoichiometric azobenzeneresulted in 22% 4k, with the remainder of the 2k being convertedto the tethered diaryl trimer that results from three diynes cyclotri-merizing. Increasing the concentration of azobenzene significantlyimproved the yield of 4k. Conversely, reaction of 3,9-dodecadiyne(2m) with only one equivalent of azobenzene gave a high yield forthe fused pyrrole 4m, highlighting that subtle changes in ring size
R
R
0.5
Cat. [Ti]
Formal [2+2+1]
N
R'
R
RR
R
R = alkyl, aryl, TMS, HR' = aryl
R'N=NR'
N
R'
R
RR
RR
R
2 + “NR'”[2+2+1]
Ti
Et
EtEt
Et
ArOOAr N
N TiN N
EtEt
Et
Et
ArO
ArON
N
(ONO)Ti
NPh Me
Me
[(ONO)TiII]N
Ph
Me
MeMe
Me
Me
Me N
(ONO)Ti
Ph
Me
Me
Me
Me
Ring contraction
Alkynetrimerization
catalyst
OAr = 2,6-diphenylphenoxide
ONO = pyridine-2,6-bis(4,6-tBu2-phenolate)
+
Rothwell
Bercaw
Reductiveelimination
This worka b
2
+
Ti NArO
ArO
N
EtEt
EtEt
N N
Figure 1 | Ti-mediated oxidative pyrrole formation. a, Previous stoichiometric examples of oxidative pyrrole formation from alkynes by Ti complexes.b, Retrosynthetic disconnection and forward reaction for catalytic formal [2+2+1] oxidative cyclization of alkynes and diazenes.
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can shift the competition to favour product formation, even at lowazobenzene concentrations.
Because the mechanisms of first and second alkyne insertions aredifferent ([2+2] addition versus migratory insertion), there is greatpotential to expand catalysis to include the selective coupling of twodifferent unsaturated substrates. For example, compared to alkynes,alkenes will not facilely undergo [2+2] reaction with Ti imidos5,41,but will rapidly undergo migratory insertion; thus it may be possibleto catalytically couple alkynes and alkenes with Ti imidos. Asexpected, tethered enyne 2n undergoes alkyne [2+2] addition fol-lowed by alkene insertion to generate an azatitanacyclohexene.However, instead of reductive C–N bond formation to yield a dihydro-pyrrole, the metallacycle rearranges before reductive elimination toyield the α,β-unsaturated imine 4n.
Coupling of untethered unsymmetrical alkynes can potentiallyyield mixtures of regioisomers. Regioselectivity is determinedduring two steps of catalysis (Fig. 4): (1) by the orientation of thealkyne during [2+2] addition to give one of two regioisomeric aza-metallacyclobutenes (A and B) and (2) during alkyne insertion,which can proceed via 1,2- or 2,1-insertion into either A or B, ulti-mately yielding one of four regioisomeric azametallacyclohexa-dienes (C, D, E or F) that then undergo reductive elimination togive the three possible pyrrole regioisomers 4, 5 and 6. Regiocontrolis highly substrate-dependent (Table 1): 2d and 2f are essentiallynon-selective for all three possible regioisomers; phenylacetylene(2g) is moderately selective for the 2,4-disubstituted regioisomer5g (4g:5g:6g = 0:4.0:1.0); and the terminal and trimethylsilyl(TMS)-protected alkynes 2e, 2h, 2i and 2j are highly selective forregioisomer 5.
The origin of selectivity in the [2+2+1] couplings of unsym-metric alkynes can be qualitatively determined by comparing the[2+2+1] regioselectivity to the selectivity of alkyne hydroaminationcatalysed by 1b, as both reactions share common [2+2] regio-isomeric metallacycle intermediates (A and B)53. Hydroaminationof tBuCCH (2i) is completely selective for the sterically preferredanti-Markovnikov imine product resulting from protonolysis ofmetallacycle B (Supplementary Section 8c). During [2+2+1] catalysiswith 2i, only 5i, which could arise from either metallacycles D or E,is observed. Based on the selectivity for B observed in the initial[2+2] step, it is likely that 5i results only from sterically preferred2,1-insertion of alkyne into B to yield metallacycle D. In the caseswhere 5 is the predominant regioisomeric product, selectivity forboth [2+2] and second insertion are controlled by alkyne sterics.
Conversely, hydroamination of phenylacetylene (2g) is less selec-tive, yielding a 1:2 mixture of the imine products resulting fromprotonolysis of A and B, respectively (Supplementary Section 8b).During [2+2+1] catalysis with 2g, products arising from metalla-cycles D, E and F are observed. In this case it is likely that theinitial [2+2] step is similarly unselective as in hydroamination,and the observed product distribution is a result of moderately selec-tive insertion of 2g into A and B, where the 2,1-addition leading tometallacycle C is disfavoured over the other insertion pathways.
Interestingly, 2d yields an unselective mixture of all three possiblepyrrole regioisomers, yet hydroamination is completely selective forthe methyl benzyl imine product that results from protonolysis ofonly one of the metallacycles. In this case, the [2+2] reaction must bereversible on the timescale of second alkyne insertion, allowing for unse-lective secondary insertion of the sterically and electronically poorlydifferentiated sides of the alkyne, yielding a mixture of all products.
Et
Et
2
10% (HNMe2)2Cl2Ti(NPh) (1a)
Mesitylene, 180 °C, 24 h
N
Ph
Et
EtEt
Et
PhN=NPh
Et
Et
Et
Et
Et
Et
EtEt
NPh
+
+
Formal [2+2+1](22%)
Trimerization(trace)
Hydroamination(10%)
HH
10% py3Cl2Ti(NPh) (1b)
PhCF3, 110 °C, 16 h
N
Ph
Et
EtEt
Et
Et
Et
Et
Et
Et
Et
++
+
Formal [2+2+1](quantitative)
Trimerization(trace)
2a
3a
4a
4a
(1)
(2)
0.5
Et
Et
2
PhN=NPh
2a
3a
0.5
Figure 2 | Initial catalytic experiments reveal that aprotic Ti imidocomplexes are highly efficient catalysts for [2+2+1] cyclization.
[LnTiII]
0.5 RN=NRDiazenedisproportionation
[2+2] addition
Insertion
Reductiveelimination
Alkynetrimerization
RN=NR LnTiIV N R
LnTiIVN
R4 R3
R2
R1R
N
R1R2
RLnTiIVN R1
R
R2R3
R4
N
N
R'
R'
LnTiIV
R1
R2
R3
R4
I
II
III
IV
V
N N
Ph
Ph
H
H
C6H6 Ti NHMe2Me2HN
N
ClCl
NPh
Δ
Ph
+ 0.5 PhN=NPh
7
TiMe2HN NHMe2
Cl Cl
N
Ph
1a
Rapid
Ti NHMe2Me2HN
N
ClCl
NPhPh
7
7
PhN
PhN NPh
NPh[Ti]
[Ti]
Dimerization “retro-[2+2+2]”
– PhNNPh “[TiII]”7
Azobenzenedecoordination
2
Comproportionation
– PhNNPh
TiMe2HN NHMe2
Cl Cl
N
Ph
1a
Independent diazene adduct synthesis and thermal disproportionation
Potential disproportionation mechanisms
TiCl2(NMe2)2
a
b
+
Figure 3 | Mechanism of Ti-catalysed formal [2+2+1] oxidative cyclizationof alkynes and diazenes. a, The reaction is proposed to proceed through aTiII/TiIV redox couple. A TiIV imido (I) undergoes [2+2] addition with an alkyneto form an azatitanacyclobutene (II). Next, a second equivalent of alkyneinserts into the azatitanacyclobutene to form an azatitanacyclohexadiene (III).Reductive elimination from III yields the pyrrole product and a TiII intermediate(IV). The resulting TiII intermediate can then either unproductively trimerizealkyne, or be trapped by azobenzene to form a TiII η2-azobenzene adduct (V),which then disproportionates into a TiIV imido (I) to close the catalytic cycle.b, Synthesis and potential mechanisms for the disproportionation of 7 to 1a.Experimental evidence indicates that the dimerization pathway is more likely.
Semi-selective (5 and 6) substratesMixture of metallacycles A and B
kAC disfavoured
Unselective (4, 5 and 6) substratesA and B mixture/formation reversible
Second insertion unselective
PhH
PhMe
tBuH
TMSnPr
nBuH
TMSH
iPrMe1,2
2,1
2,1
1,2
Figure 4 | Mechanistic scheme explaining selectivity differences between various unsymmetric alkynes. The orientation of the alkyne during [2+2]addition results in two possible regioisomeric azametallacyclobutenes: A and B. The alkyne insertion, which can proceed via 1,2- or 2,1-insertion into either Aor B, ultimately yields one of four regioisomeric azametallacyclohexadienes (C, D, E or F) that then undergo reductive elimination to give the three possiblepyrrole regioisomers 4, 5 and 6.
Conditions: 1.21 mmol 2 (6 equiv.), 0.20 mmol 3 (1 equiv.), 0.020 mmol 1b (0.1 equiv.), 1 ml CF3Ph, 16 h; *NMR yield based on 3a with Ph3CH internal standard; †apparent turnover frequency based on initialrates is ∼1 h−1; ‡6 equiv. 3a; yield based on 2; §overlapping 1H NMR signals prevent accurate integration: >80% 5h; ||isolated yield upon hydrolysis to the corresponding ketone.
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Further substrate scope analysis was performed using substitutedaryl diazenes (Table 2). Tolyl-substituted diazenes 3b and 3c reactedsimilarly to the parent azobenzene; however, more sterically encum-bered diazene 3d was lower yielding. Electron-rich diazene 3e, whichcontains a heteroatom-functionalized arene, also gives excellent con-version to 4ae. Of synthetic importance, the N-methoxyphenyl sub-stituent in 4ae can potentially be oxidatively deprotected to yieldthe N-unsubstituted pyrrole. Finally, using an asymmetric diazene(3i) yields both products 4a and 4ai in a 1:1 ratio, indicating bothhalves of the diazene are incorporated into the pyrroles at aroughly equal rate.
In summary, a simple Ti imido precatalyst, py3Cl2Ti(NPh), iscapable of performing inter- and intramolecular oxidative couplingof alkynes or enynes with diazenes to generate polysubstituted pyr-roles. This reaction is a unique example of catalytic oxidative C–Nbond formation with a group 4 early transition metal and of cata-lytic formal [2+2+1] six-electron cyclization with a nitrene feed-stock. A key feature of the catalytic cycle is the cleavage of theN=N double bond of an aryl diazene, which occurs through thedisproportionation of a TiII η2-diazene adduct to reform a TiIV
imido. Initial studies have revealed that the regioselectivity of thealkyne coupling is under substrate control. However, given recentsuccesses in ligand development for selective and functionalgroup-tolerant early transition-metal-catalysed Pauson–Khand54
and hydroamination5,55 reactions, it may be possible to applysimilar principles to advance substrate scope and selectivity inthe catalytic formal [2+2+1] reaction.
Received 10 June 2015; accepted 29 September 2015;published online 2 November 2015; corrected online2 December 2015
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Table2 | Initial diazene scope of Ti-catalysed formaloxidative [2+2+1] cyclization.
310% py3Cl2Ti(NPh) (1b)
PhCF3, 140 °C, 16 h
N
R
Et
EtEt
EtRN=NR'
2a 3b–3i 4
0.5Et Et
Entry
1
Diazene Product
NN
NN2
3
4
5
6
7
8
3b
3c
N
N
N
N
N
N
N
N
N
NN
N 3dtBu
tBu
tBu
tBu
MeO
OMe
3e
F3C
3f
NMe2
CF3
3i
OiPriPrO
O
O
3g
3h
4ae R = 4-MeOPh
No reaction
4ac R = Bn
No reaction
4a:4ai (1:1)
%Yield (NMR)*
85 (86)
71 (83)
(32)
66 (86)
(69)
4ac R = 2-MePh
4ab R = 4-MePh
4ad R = 3,5-di- BuPht
Trace†
+
Conditions: 1.21 mmol 2 (6 equiv.), 0.20 mmol 3 (1 equiv.), 0.020 mmol 1b (0.1 equiv.), 1 ml CF3Ph,16 h; *NMR yield based on 3a with Ph3CH internal standard; †Bn2N2 undergoes radicaldecomposition under the reaction conditions.
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AcknowledgementsFinancial support was provided by the University of Minnesota (start-up funds).Equipment purchases for the Chemistry Department NMR facility were supported by agrant from the National Institutes of Health (S10OD011952) withmatching funds from theUniversity of Minnesota. The Bruker-AXS D8 Venture diffractometer was purchasedthrough a grant from NSF/MRI (1224900) and the University of Minnesota.
Author contributionsZ.W.G. and I.A.T. conceived and designed the experiments. Z.W.G. and R.J.H. performedthe experiments and analysed the data. I.A.T. wrote the manuscript. All authorscontributed to revising the manuscript.
Additional informationSupplementary information and chemical compound information are available in theonline version of the paper. Reprints and permissions information is available online atwww.nature.com/reprints. Correspondence and requests for materials should beaddressed to I.A.T.
Competing financial interestsThe authors declare no competing financial interests.
ARTICLES NATURE CHEMISTRY DOI: 10.1038/NCHEM.2386
NATURE CHEMISTRY | VOL 8 | JANUARY 2016 | www.nature.com/naturechemistry68
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