Oxidative nitrene transfer from azides to alkynes via Ti(ii)/Ti(iv) redox catalysis: Formal [2+2+1] synthesis of pyrroles

Article abstract of DOI:10.1039/c8cc02623h

Catalytic oxidative nitrene transfer from azides with the early transition metals is rare, and has not been observed without the support of redox noninnocent spectator ligands. Here, we report the formal [2+2+1] coupling of azides and alkynes via Ti^II/Ti^IV redox catalysis from simple Ti halide imido precatalysts. These reactions yield polysubstituted N-alkyl pyrroles, including N-benzyl protected pyrroles and rare examples of very electron rich pentaalkyl pyrroles. Mechanistic analysis reveals that [2+2+1] reactions with bulky azides have different mechanistic features from previously-reported reactions using azobenzene as a nitrene source.

Full text of DOI:10.1039/c8cc02623h

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Oxidative Nitrene Transfer from Azides to Alkynes via Ti(II)/Ti(IV)
Redox Catalysis: Formal [2+2+1] Synthesis of Pyrroles
Adam. J. Pearce, Xin Yi See, and Ian A. Tonks*
1Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
Catalytic oxidative nitrene transfer from azides with the early
transition metals is rare, and has not been observed without the
support of redox noninnocent spectator ligands. Here, we report
the formal [2+2+1] coupling of azides and alkynes via TiII/TiIV redox
catalysis from simple Ti halide imido precatalysts. These reactions
yield polysubstituted N-alkyl pyrroles, including N-benzyl protected
pyrroles and rare examples of very electron rich pentaalkyl
pyrroles. Mechanistic analysis reveals that [2+2+1] reactions with
bulky azides have different mechanistic features from previously-
reported reactions using azobenzene as a nitrene source.
success of this reaction is predicated on the ability of Ti to
backbond into the substrates and/or the products, either of which
can act as a π-acceptor to mask the TiII species. Inspired by the
successes of Wolczanski and Heyduk in RNI-promoted catalytic
oxidative nitrene transfer from azides with group 4 metals, we
sought to investigate the use of azides in [2+2+1] pyrrole
synthesis in the absence of an engineered RNI ligand.
Heyduk (2011):
tBuNC
+ RN3
MeO
MeO
iPr
iPr
NtBu
N
N
N
C
ZrIV
Cl
ZrIV
Cl
N
NR
N
Nitrene transfer reactions are powerful tools for functional
group installation in organic chemistry. For example, transition
metal-catalyzed nitrene transfer, particularly with late transition
metals, has been used frequently in alkene aziridinations1 and C-
H functionalizations.2 Due to the thermodynamic stability of the
d0 configuration, early transition metal-mediated nitrene
transfers are rare3 and predominately stoichiometric. Recently,
major successes has been achieved in employing redox non-
innocent (RNI) ligands to stabilize the early transition metals in
their d0 state, allowing the metal to act as a conduit for electron
N
iPr
iPr
MeO
MeO
(NNN)3-
(NNN)1-
tBuN=C=NR
AdN3
Wolczanski (2017):
AdNCO
O
C
Ad
Ad
N
N
N
N
N
N
TiIV
TiIV
5
transfers that are ligand-centered. Both the Heyduk4b, and
N
N
N
N
Ar
Ar
Wolczanski6 groups have developed catalytic reactions with RNI
ligand scaffolds and organic azides to allow for facile nitrene
transfer that could be used in small molecule
synthesis/functionalization (Figure 1).
Ar
Ar
(dadi)4-
(dadi)2-
CO (3.7 atm)
Figure 1. Nitrene transfer reactions catalyzed by early transition
metal/redox noninnnocent ligand systems.
Recently, we reported the Ti-catalyzed formal [2+2+1]
multicomponent coupling of alkynes and aryl diazenes for the
synthesis of penta- and trisubstituted pyrroles, which at the time
was the first example of catalytic nitrene transfer from Ti.7 In the
absence of ancillary RNI ligands, we hypothesize that the
Although organic azides are well-known to undergo Huisgen
cycloadditions with alkynes to form triazoles—either thermally8
or with myriad metal catalysts9—we hypothesized that TiII
intermediates generated in the reaction would be sufficiently
reactive to reduce the azide and turn over the catalytic cycle at
rates competitive with this potential background reaction.
Further, organic azides offer several advantages over diazenes.
For example, alkyl azides—unlike alkyl diazenes—are typically
stable above 130 °C and thus could allow access to N-alkyl
pyrroles, allowing for installation of N-protecting groups on the
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 1
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pyrrole.10 This would also give access to pentaalkyl pyrroles, By moving to a more Lewis acidic catalyst (THF) TiI (Ntol),
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3
2
DOI: 10.1039/C8CC02623H
which are extremely rare structures due to their oxidative which more indiscriminately binds ligands, the desired pyrrole
instability and difficulty of synthesis.11 Additionally, many product 3ba was formed in 80% yield with no detectable azide
diazenes are made from azides,5b, 12 so direct use of azides could decomposition side-products (eq 2).
streamline precursor synthesis. A wide variety of organic azides
Kinetic analysis of the (THF)3TiI2(Ntol)-catalyzed reaction
are also easily accessed through simple substitution chemistry, of 1b with 2a through variable time normalization analysis15
providing a more straightforward method for synthesizing yields the rate law in Figure 3 (top). Assuming a mechanistic
complex N-substituted pyrroles.13 Herein, we report that organic manifold similar to [2+2+1] pyrrole formation with azobenzene
azides are competent reaction partners for Ti-catalyzed formal as the nitrene source7a, 7d the 2nd order dependence of 3-hexyne
[2+2+1] pyrrole synthesis and related oxidative multicomponent indicates that 2nd insertion of 2a into the azatitanacyclobutene
alkyne aminations. These reactions provide access to N-alkyl intermediate II is the rate-determining step of catalysis.
functionalized products, in contrast to previously-described
AdN3 (1b): rate
∝
[Ti][EtCCEt]2 DecN3 (1c): rate
∝
[Ti]0.5[EtCCEt]2[DecN3]-0.5
methods which were limited to N-arylated products.7d
PhNNPh: rate
∝
[Ti]0.5[EtCCEt]2[PhNNPh]-1
p-tol
Et
Et
10% py3TiCl2(NtBu)
N
R
N
R
N
R
Et
Et
Et
Et
R
Et
Et
[2+2]
insertion
p-tolN3
+
N
LnTiIV
TiIVLn
N
C6D5Br, 115 o
16 h
C
Et
RDS
IV
N
R
LnTiIV
TiIV
L
Ti
n
Ln
Et
Et
3aa
1a
2a
16%
Low Yielding
Dimerization relevant
for R = Ph, decyl
I
II
1 equiv.
5 equiv.
III
Et
R
Et
N
6aa
21%
Uncatalyzed
[3+2]
7a
40%
Ti-catalyzed
hydroamination
(From tolNH2)
8a
< 5%
Nitrene
coupling
p-tol
p-tol
Et
red.
elim.
p-tol
Et
Et
N
R
N
N
N
“TiII”
Et
+
Et
N
N
Et
Et
LnTiII
cycloaddition
Et
Et
N
p-tol
Et
Et
IV
Byproducts from background thermal azide reactivity
faster
slower
PhNNPh
AdN3
Figure 2. Top: initial reaction attempts of 1a and 2a catalyzed by
py3TiCl2(NtBu) were marred by azide decomposition.
Ph
N
LnTiIV
N
Et6
Initial coupling attempts of p-tolyl azide (1a) with 3-hexyne
LnTiII(N3Ad)
(
2a) catalyzed by 10% py3TiCl2(NtBu) in C6D5Br at 115
°C
Ph
competitive
cyclotrimerization
(observed with PhNNPh)
yielded 16% of the desired pyrrole product, 2,3,4,5-tetraethyl-N-
(p-tolyl) pyrrole (3aa). However, this reaction is marred by
significant side-product formation: 4,5-diethyl-1-(p-tolyl)-1H-
1,2,3-triazole, (6a), N-(p-tolyl)hexan-3-imine, (7a), and 4,4’-
azotoluene (8a). All of the sideproducts in this reaction can be
ascribed to thermal azide decomposition—6a from the
NPh
- N2
PhN
Ph
N
LnTiIV
Ph
N
0.5
TiIVLn
Ad
N
LnTiIV
N
Ph
LnTiIV
0.5 PhNNPh
uncatalyzed [3+2] Huisgen condensation of 1a with 2a; 7a from
bimetallic reoxidation with diazenes
mandates dimer structure
monometallic
reoxidation with azides
the Ti-catalyzed hydroamination of 2a with aniline, which is
formed during azide decomposition to the free nitrene; and 8a
from thermal azide coupling.14
Figure 3. Comparison of the mechanisms of pyrrole formation with
azide or azobenzene reveal different mechanisms of reoxidation.
N3
Ad
Et
However, the remainder of rate law for 1b is different from
the azobenzene reaction (Figure 3, top). With 1b, the reaction is
1st order [Ti], in contrast to 0.5 order [Ti] in azobenzene
reactions. This indicates that Ti dimerization is not kinetically
relevant, unlike in azobenzene reactions where an on-cycle dimer
is required for catalyst reoxidation to occur. This also indicates
that the Ti=NAd group is sterically bulky enough to avoid off-
cycle dimerization, which is often kinetically relevant in Ti
imido-catalyzed reactions.16 The zero-order dependence on 1b
indicates that TiII oxidation is fast compared to alkyne insertion,
and that sterically-encumbered 1b doesn’t inhibit catalysis
through competitive binding to Ti, where PhNNPh does. In
contrast, substituting 1b for n-decN3 (1c) gives a reaction that is
0.5 order [Ti], as well as -0.5 order [decN3]. This observation
further indicates that steric bulk prevents dimerization and azide
10% py3TiCl2(NtBu)
N
Et
Et
+
(1)
C6D5Br, 115 o
16 h
C
Et
Et
Et
3ba
8%
1b
2a
2 equiv.
1 equiv.
N3
Low conversion
Ad
Et
10% (THF)3TiI2(Ntol)
N
Et
Et
+
(2)
C6D5Br, 115 o
16 h
C
Et
Et
Et
3ba
80%
No sideproducts
1b
2a
1 equiv.
5 equiv.
Attempts to improve the selectivity and yield of this reaction
through reaction optimization only marginally improved
catalysis, and as a result alkyl azides were explored. Alkyl azides
are significantly more thermally robust than aryl azides and
undergo [3+2] addition more slowly, and are thus less likely to
undergo competitive decomposition under catalytic conditions.
Reaction of adamantyl azide (1b) with 2a catalyzed by 10%
inhibition in reactions with 1b
.
Next, the scope of internal alkynes was investigated (Table
1). Simple internal alkyl alkynes 3-hexyne (2a) and 2-butyne
py3TiCl2(NtBu) in C6D5Br at 115
°C resulted in low conversion,
(
2b) give high yields; however, diphenylacetylene (2c) yields no
presumably due to inhibition of alkyne binding by azide (eq 1).
product. In these with excess alkyne, trimerization of the
2 | J. Name., 2012, 00, 1-3
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remaining alkyne can occur after productive catalysis is tendency for primary metal-imidos to dimerize.16c They are also
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complete. By shortening reaction times to 2h (Entry 2), lower but better nucleophiles, which could hinDdOerI: 10c.a1t0a3l9y/sCi8sCCth0r2o6u23gHh
satisfactory yields can still be obtained in the absence of coordination to Ti, akin to hydroamination reactions with
trimerized byproducts. 1-phenyl-1-propyne (2d) gives a 1.6 : 1 primary alkyl amines.18 Nonetheless, n-decyl azide (1c) gives
mixture of regioisomeric pyrroles 3bd and 4bd in high yield. moderate yield of pentaalkyl pyrroles (Table 1 entries 6-9).
This is in contrast to the reaction of 2d with PhNNPh, which
In reactions of 1c, small amounts of 1-iododecane are formed
yields all three possible pyrrole regioisomers in a statistical along with the 3ca. This likely forms through SN2 of N3 of by
distribution:7d with 1b, the stereoelectronic effect17 of the N-adl iodide, forming a titanium azido complex. Reaction of TMSN3
group prevents [2+2] cycloaddition with the aryl of 2d oriented with Ti halide catalysts similarly yields TMS-halides and
toward NAd, which is required for the formation of 5d
.
unreactive Ti azido species. Given this observation, we
suspected that the lower yields of 1c were a result of catalyst
death; indeed, when additional 1c was added at the end of the
reaction, no additional product formed. However, reducing the
concentration, decreasing the reaction time, and using excess 2a
results better yields with respect to 1c (entry 9).
Benzyl azide (1d) gives good yields in the coupling with 2a
(entry 10)—potentially allowing access to NH pyrroles through
hydrogenolysis of the resulting benzyl protecting group. Aryl
azides still perform poorly even at high alkyne and catalyst
loading due to their propensity to undergo uncatalyzed [3 + 2]
cycloadditions and thermal decomposition (entries 11 and 12).
(THF)3TiI2(Ntol) rapidly cyclotrimerizes terminal alkynes,19
which bind faster and stronger to Ti than internal alkynes.
Accordingly, we returned to the less-active py3TiCl2(NtBu) for
[2+2+1] of azides with terminal alkynes (Table 2). At a 2:1
Table 1. Internal alkyne scope.
R1
R3
10% (THF)3TiI2(Ntol)
C6D5Br, 115 o
N
R2
R3
R1N3
+
C
R2
R3
R2
3
(+ isomers for 3d)
1
2
En-
try
1b
Azide
Alkyne
Alkyne
equiv.
5
t
(h)
16
% Yield
(NMR)
Et
Et
Et
Et
Ad
1b
Ad
1b
Ad
1b
Ad
1b
Ad
1b
n-dec
1c
n-dec
1c
n-dec
1c
n-dec
1c
Bn
1d
tol
(80)
2a
2a
2c
3b
5
5
5
5
3
3
3
5
5
5
8
5
5
2
16
16
16
6
23 (59)
(94)
trace
(70)d
(37)
(35)
(42)
48 (64)
59 (62)
(30)
(52)
0
Me
Ph
Ph
Et
Et
Et
Et
Et
Et
Et
Et
Et
Me
2b
2c
2d
2a
2a
2a
2a
2a
2a
2a
2a
2a
4b
Ph
Me
Et
Et
Et
Et
Et
Et
Et
Et
Et
alkyne : azide stoichiometry, simple alkyl (2e) and aryl (2f
)
acetylenes give moderate yields of pyrroles along with small
amounts (typically < 20% yield) of trimerization. In contrast,
reactions with azobenzene as the nitrene source require
significant excesses of azobenzene (1 : 4 alkyne : azobenzene) to
suppress trimerization. This indicates that azides are
significantly better at intercepting TiII intermediate IV than
5b
6ce
7cf
8c
6
azobenzene,
imparting
post-rate-determining-step
6
chemoselectivity for pyrrole formation over alkyne trimerization
(Figure 3).
9c
2
Terminal alkynes could potentially give 3 regioisomeric
trisubstituted pyrroles
adamantyl group completely impedes the formation of the 2,5-
disubstituted pyrroles . Reaction of p-tolylacetylene (2f, entry
3, 4 and 5. In all cases, the size of the
10c
11c
12g
13c
14c
2
5
2
2) shows a 1 : 1 mixture of 3bf : 4bf, a contrast to the product
distribution observed using azobenzene as the nitrene source,
which yields 3 : 4 in a 4 : 1 with phenylacetylene.1 This further
demonstrates that bulky alkyl imidos bias the reaction toward
trisubstituted products where the substituents are pointed away
1a
tol
1a
3
PhSCH2
1e
Ph3C
2
from N such as 4. With a bulky alkyne substrate such as t-
2
0
butylacetylene (1g), no reaction was observed with 1b. With less
bulky p-tolyl azide (1a), pyrrole formation can be observed in
low yield, albeit with significant nitrene decomposition products
1f
aNMR yield calculated with respect to
bConditions: 0.2 mmol 1b, 1.0 mmol
115˚C, 0.5 mL C6D5Br, average of 2 runs. cConditions: 0.1 mmol
1
with Ph3CH internal standard.
2
, 10 mol % (THF)3TiI2(Ntol)
(vide supra). Similarly, bulky (trimethylsilyl)acetylene (2h
)
1, 2a,
gives low pyrrole yields, as [3+2] cycloaddition and
cyclotrimerization better compete with the productive reaction.
In summary, simple Ti catalysts are capable of affecting
oxidative nitrene transfer reactions with azides and alkynes to
generate pyrroles. This reaction is only the 2nd example of Ti-
catalyzed nitrene transfer from an azide, and a rare example of
2-electron group 4 redox catalysis. Unlike previous examples of
group 4-catalyzed oxidative nitrene transfer from azides, this
10 mol % (THF)3TiI2(Ntol), 115˚C, 2 h, 0.5 mL C6D5Br, average of 2-3
runs. d1.6 : 1.0 : 0 ratio of 3bd : 4bd : 5bd eConducted at 80 ˚C.
fConducted at 100 ˚C. gConditions: 0.1 mmol 1a, 0.8 mmol
2, 10 mol %
(THF)3I2Ti(Ntol), 115˚C, 0.5 mL C6D5Br.
In the pursuit of accessing N-protected pyrroles, we sought
to expand the azide scope in the system. Primary alkyl azides
such as n-decyl azide (1c) are challenging because of the
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9792-9796; (c) Roizen, J. L.; Harvey, M. E.; Du Bois, J. Acc. Chem.
DOI: 10.1039/C8CC02623H
Res. 2012, 45, 911-922; (d) A., I. D.; T., W. M. J.; Yunjung, B.; T., H.
reaction does not require ancillary redox noninnocent ligands
and instead relies on “classical” redox noninnocence through
backbonding into the substrates and products, albeit at the cost
of potentially higher reaction temperatures.
Table 2. Terminal alkyne scope.a
View Article Online
p
-
E.; A., B. T. Angew. Chem., Int. Ed. 2017, 56, 15599-15602.
3. Basuli, F.; Aneetha, H.; Huffman, J. C.; Mindiola, D. J. J. Am.
Chem. Soc. 2005, 127, 17992-17993.
4. (a) Ballmann, J.; Pick, F.; Castro, L.; Fryzuk, M. D.; Maron, L.
Inorg. Chem. 2013, 52, 1685-1687; (b) Munha, R. F.; Zarkesh, R. A.;
Heyduk, A. F. Dalton Trans. 2013, 42, 3751-3766.
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A.; Lacy, D. C.; Thorson, M. K.; Heyduk, A. F. Chem. Sci. 2011, 2, 166-
169.
R1
R1
R1
H
10% py3TiCl2(NtBu)
N
N
N
R2
R2
R2
R1N3
+
2.1
R2
+
+
C6D5Br, 115 o
C
R2
R2
R2
4
5
3
1
2
% Yield 3 – 5
(3 : 4 : 5)
Entry
R1
Alkyne
Ad
1b
nBu
H
65
6. Heins, S. P.; Wolczanski, P. T.; Cundari, T. R.; MacMillan, S. N.
Chem. Sci. 2017.
1
(1.0 : 0.2 : 0)
2e
2f
7. (a) Davis-Gilbert, Z. W.; Wen, X.; Goodpaster, J. D.; Tonks, I. A.
Submitted (b) Chiu, H.-C.; Tonks, I. A. Angew. Chem., Int. Ed, doi:
10.1002/anie.201800595; (c) Davis-Gilbert, Z. W.; Yao, L. J.; Tonks, I.
A. J. Am. Chem. Soc. 2016, 138, 14570-14573; (d) Gilbert, Z. W.;
Hue, R. J.; Tonks, I. A. Nat. Chem. 2016, 8, 63-68.
H
66
2
Ad
(1.0 : 1.0 : 0b)
tol
1a
tBu
H
7
3
4
(1.0 : 0 : 0)
2g
2h
TMS
H
8. Huisgen, R., 1,3-Dipolar cycloaddition chemistry. Wiley, New
York: 1984.
Ad
1b
34
(1.0 : 0 : 0)
9. (a) Meldal, M.; Tornøe, C. W. Chem. Rev. 2008, 108, 2952-3015;
(b) Boren, B. C.; Narayan, S.; Rasmussen, L. K.; Zhang, L.; Zhao, H.;
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10. (a) Engel, P. S. Chem. Rev. 1980, 80, 99-150; (b) L'Abbe, G.
Chem. Rev. 1969, 69, 345-363.
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23, 1335-1338.
Ad
1b
38
n/a
5c
2i
aConditions : 0.2 mmol 1 (1 equiv.), 0.42 mmol
2
(2.1 equiv.), 10 mol
% py3TiCl2(NtBu), 115 °C, 6 h, 0.5 ml C6D5Br, average of 2 runs
bProduct ratio determined by quantitative GC-FID. c0.21 mmol 2i
.
This protocol allows access to N-alkylpyrrole derivatives, in
complement to previously-reported Ti-catalyzed [2+2+1]
pyrrole syntheses with diazenes, which were limited to N-aryl
pyrroles. There are several examples of highly substituted N-
alkyl pyrroles with important bioactivity, such as atorvastatin.20
These azide reactions also have contrasting mechanistic features
to the diazene reactions: for example, azide reactions can
effectively outcompete alkyne cyclotrimerization, even with
highly reactive terminal alkynes. Furthermore, azide reactions do
not require a dimeric species to undergo reoxidation, changing
the rate dependence of catalyst concentration when compared to
diazene reactions. The mechanistic insight herein provides a
platform for the further development of Ti-catalyzed oxidative
amination reactions into practical methods.
Financial support was provided by the National Institutes of
Health (1R35GM119457) and the Alfred P. Sloan Foundation
(Sloan Fellowship for IAT). Equipment purchases for the NMR
facility were supported from the NIH (S10OD011952) with
matching funds from the University of Minnesota. The authors
declare no competing financial interests.
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4 | J. Name., 2012, 00, 1-3
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DOI: 10.1039/C8CC02623H
Abstract Picture
p-tolyl
N
THF
I
I
Ti
pentaalkyl pyrroles
THF
THF
R
R'
• simple Ti catalysts
• good yields
N
R'
R'
via TiIV TiII
RN3
+
2
• access to electron-rich pyrroles
R'
R'
R = alkyl, benzyl, aryl
R'