Cobalt-Porphyrin-Catalysed Intramolecular Ring-Closing C?H Amination of Aliphatic Azides: A Nitrene-Radical Approach to Saturated Heterocycles

Article abstract of DOI:10.1002/chem.201700358

Cobalt-porphyrin-catalysed intramolecular ring-closing C?H bond amination enables direct synthesis of various N-heterocycles from aliphatic azides. Pyrrolidines, oxazolidines, imidazolidines, isoindolines and tetrahydroisoquinoline can be obtained in good to excellent yields in a single reaction step with an air- and moisture-stable catalyst. Kinetic studies of the reaction in combination with DFT calculations reveal a metallo-radical-type mechanism involving rate-limiting azide activation to form the key cobalt(III)-nitrene radical intermediate. A subsequent low barrier intramolecular hydrogen-atom transfer from a benzylic C?H bond to the nitrene-radical intermediate followed by a radical rebound step leads to formation of the desired N-heterocyclic ring products. Kinetic isotope competition experiments are in agreement with a radical-type C?H bond-activation step (intramolecular KIE=7), which occurs after the rate-limiting azide activation step. The use of di-tert-butyldicarbonate (Boc₂O) significantly enhances the reaction rate by preventing competitive binding of the formed amine product. Under these conditions, the reaction shows clean first-order kinetics in both the [catalyst] and the [azide substrate], and is zero-order in [Boc₂O]. Modest enantioselectivities (29–46 % ee in the temperature range of 100–80 °C) could be achieved in the ring closure of (4-azidobutyl)benzene using a new chiral cobalt-porphyrin catalyst equipped with four (1S)-(?)-camphanic-ester groups.

Full text of DOI:10.1002/chem.201700358

A Journal of
Accepted Article
Title: Nitrene-radical approach to Saturated Heterocycles; Cobalt
Porphyrin Catalysed Intramolecular Ring-Closing C-H Amination
of Aliphatic Azides
Authors: Bas de Bruin, Petrus F. Kuijpers, Martijn J. Tiekink, Willem B.
Breukelaar, Daniël L. J. Broere, Nicolaas P. van Leest, Jarl
Ivar van der Vlugt, and Joost N. H. Reek
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To be cited as: Chem. Eur. J. 10.1002/chem.201700358
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Nitrene-radical approach to Saturated Heterocycles; Cobalt
Porphyrin Catalysed Intramolecular Ring-Closing CH Amination
of Aliphatic Azides
Petrus F. Kuijpers, Martijn J. Tiekink, Willem B. Breukelaar, Daniël L. J. Broere, Nicolaas P. van Leest,
Jarl Ivar van der Vlugt, Joost N. H. Reek and Bas de Bruin*
Abstract: Cobalt porphyrin catalysed intramolecular ring-closing CH
bond amination enables direct synthesis of various N-heterocycles
from aliphatic azides. Pyrrolidines, oxazolidines imidazolidines,
isoindolines and tetrahydroisoquinoline can be obtained in good to
excellent yields in a single reaction step with an air and moisture
stable catalyst. Kinetic studies of the reaction in combination with DFT
calculations reveal a metallo-radical-type mechanism involving rate
limiting azide activation to form the key cobalt(III)-nitrene radical
intermediate. Subsequent low barrier intramolecular HAT from a
benzylic CH bond to the nitrene-radical intermediate followed by a
radical rebound step leads to formation of the desired N-heterocyclic
ring products. Kinetic isotope competition experiments are in
N-heterocyclic compounds, but to date most of the reported
protocols are limited to the use of electronically pre-activated
azides.[9-12] More recently, and most relevant to the investigations
described in this paper, some interesting examples involving
intramolecular amination of CH bonds using primary aliphatic
organic azides (RCH2N3) as the ‘nitrene’ source were reported
(see Figure 1).[13-15]
agreement with
a
radical-type CH bond activation step
(intramolecular KIE = 7), which occurs after the rate limiting azide
activation step. The use of di-tert-butyl dicarbonate (Boc2O)
significantly enhances the reaction rate by preventing competitive
binding of the formed amine product. Under these conditions, the
reaction shows clean first order kinetics in both the [catalyst] and the
[azide substrate], and is zero order in [Boc2O]. Modest
enantioselectivities (2946% ee in the temperature range between
10080 C) could be achieved in the ring closure of (4-
azidobutyl)benzene using a new chiral cobalt porphyrin catalyst
equipped with four (1S)-()-camphanic-ester groups.
Introduction
Organic azides are interesting nitrene precursors for direct CH
amination reactions, producing linear or cyclic amines and only N2
as a harmless side product.[1,2] For example, Warren and
coworker reported on the Cu-catalyzed activation of adamantyl
azide, followed by intermolecular nitrene insertion into several
different CH bonds.[3] In general, however, most reported CH
amination examples involve activation of electronically pre-
activated and/or bulky, sterically protected tertiary azide
t
substrates, such as BuN3, adamantly azide, aryl azides (ArN3),
Figure 1. Comparison of previously reported catalysts and those used in the
present study for intramolecular ring-closing CH bond amination taking
(4-azidobutyl)benzene as a benchmark.
phosphoryl azides ((RO)2(O)PN3), sulfonyl azides (RSO2N3) or
carbonazidates (RO(CO)N3) as the nitrene-precursors.[1-8]
Intramolecular CH amination reactions involving organic azides
constitutes an interesting protocol for the preparation of
While these examples provide interesting lead-reactivity for the
synthesis of saturated heterocycles (in particular the system
reported by Betley and coworkers[13a]), there are still a number of
hurdles to overcome: (1) All of the currently reported catalysts for
this reaction are highly sensitive to air and water and require
relatively high catalyst loadings, thus resulting in low catalytic
turnover numbers (TONs).[13-15] (2) Several of the reported
catalysts produce significant amounts of (Boc-protected) linear
amines as undesired side products.[13-15] (3) Asymmetric versions
of intramolecular ring-closing CH bond amination reactions of
unactivated aliphatic azides are unknown. (4) Only limited
[a]
P. F. Kuijpers, M. J. Tiekink, W.B. Breukelaar, Dr. D. L. J. Broere,
N.P. van Leest, Dr. Ir. J. I. van der Vlugt, Prof. Dr. J. N. H. Reek and
Prof. Dr. B. de Bruin
Van ‘t Hoff Institute for Molecular Sciences (HIMS)
University of Amsterdam (UvA)
Science Park 904, 1098 XH Amsterdam, The Netherlands
E-mail: b.debruin@uva.nl
Supporting information for this article is given via a link at the end of
the document.((Please delete this text if not appropriate))
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mechanistic information for these types of reactions is available
to guide scientists in finding solutions to the above challenges,
thus hampering the design and development of more efficient
catalysts. Reported mechanistic proposals for these types of
reactions are quite interesting. Based on spectroscopic studies
and supporting DFT calculations, activation of electronically pre-
activated organic azides (i.e. CH3C6H4SO2N3 (TsN3),
NO2C6H4SO2N3 (NsN3), CCl3CH2O(C=O)N3 (TrocN3)) by cobalt(II)
porphyrin catalysts is believed to produce unique cobalt(III)
nitrene-radical intermediates (CoIIIN•Y), which subsequently
react with CH bonds in a hydrogen atom transfer (HAT) radical
rebound process.[16] Related nitrene-radical intermediates (albeit
with more complicated electronic structures) have been proposed
as intermediates in the Fe- and Pd-catalysed formation of
N-heterocycles from (4-azidobutyl)benzene.[13-15] However,
kinetic and/or spectroscopic evidence to unambiguously support
these mechanistic proposals is thus far lacking. Furthermore, the
mechanism of activation of primary aliphatic azides might differ
from the catalytic pathways followed by more activated organic
azides such as NsN3 and TrocN3 (also for cobalt-based catalysts).
Results and Discussion
We started our evaluation of the catalytic activity of cobalt(II)
porphyrin complexes under various conditions by monitoring the
conversion of azide 5a into pyrrolidine 5b (Table 1) with the
commercially available cobalt(II) tetraphenylporphyrin complex 1
([Co(TPP)], Figure 2).
Figure 2. Achiral cobalt(II) complexes used in this study: cobalt(II)
tetraphenylporphyrin ([Co(TPP)], 1), cobalt(II) pentafluorophenylporphyrin
([Co(TPF20P)], 2), cobalt(II) tetramesitylporphyrin ([Co(TMP)], 3), and cobalt(II)
salophen ([Co(salophen], 4).
Alternative resting states and rate limiting steps may be
operational, and the CH activation steps could either involve a
HAT-rebound mechanism, direct nitrene insertion into the CH
bond, or even both at the same time.[13a] Moreover, as the
activation of aliphatic azides typically requires elevated reaction
temperatures, even the involvement of free nitrene intermediates
in the CH bond amination steps cannot be excluded.[17] Hence,
the mechanistic features previously disclosed for reactions
involving activated azides cannot be directly translated to those
involving much less reactive aliphatic azides. As such we became
interested in the activation of primary aliphatic azides by low-spin,
metalloradical cobalt(II) catalysts, which has never been reported
to the best of our knowledge. Herein we disclose and discuss the
cobalt(II) porphyrin catalysed ring-closing CH bond amination of
primary aliphatic azides, focusing in particular on the mechanism,
scope and prospect of these reactions (see Figure 1).
In the absence of an amine trapping agent, complete recovery of
the starting material was observed after 16 hours at 100 °C using
1 mol% of the catalyst (Table 1, entry 1).
Table 1. Catalyst evaluation in intramolecular ring-closing CH bond amination
of azide 5a.[a]
Entry
Catalyst
Loading
(mol%)
Conversion
(NMR)
Yield
(isolated)
TON
1[d]
2
[Co(TPP)]
[Co(TPP)]
[Co(TPF20P)]
[Co(TMP)]
[Co(TMP)]
[Co(TMP)]
[Co(Salophen)]
AIBN
1
1
1
1
1
1
1
4
2
4
-
-
n.d.[c]
17
[b]
[b]
The catalysts reported herein are air and water stable, and cleanly
produce cyclic (Boc-protected) amines in good yields and with
higher TONs than reported for other catalysts. Additionally,
detailed mechanistic information was gathered from reaction
progress kinetics, kinetic isotope competition experiments and
supporting DFT studies, which strongly support the involvement
of aliphatic CoIIIN•R species as key intermediates in these
reactions. Furthermore, as a proof of principle, we here present
the first example of an enantioselective CH amination reaction
of the type shown in Figure 1, suggesting strongly that the CH
bond activation and CN bond formation steps of the overall
catalytic ring-closing reaction occur in the coordination sphere of
cobalt. No free nitrene intermediates seem to be involved in these
reactions.
24%
<5%
38%
39%
30%
 [b]
17%
n.d.[c]
36%
32%
n.d.[c]
 [b]
n.d.[c]
35
3
4
5[e]
6[f]
7[g]
8
30
30
n.d [c]
n.d [c]
27
 [b]
 [b]
57%
>95%
54%
89%
9
[Co(TMP)]
[Co(TMP)]
21
10
[a] Conditions: Substrate 5 (0.3 mmol), catalyst (1-4 mol%), Boc2O (0.36 mmol)
and solvent (3.0 mL) were mixed and reacted for 16 h at 100 °C. After the
reaction only starting material and expected products were observed. [b] No
product was detected by 1H-NMR. [c] Not determined. [d] no Boc2O was used
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in the reaction. [e] Benzene was used as the solvent. [f] 3 vol% water was
present in the solvent. [g] Salophen = N,N''-bis-(3,5-di-tert-butyl-salicylidene)-
1,2-phenylenediamine).
aliphatic chain at the alpha-position to the benzylic CH (Table 2,
entry 1, 6a), the oxazolidine product was obtained in high isolated
yield (6b, 93%; TON = 23). Introduction of two methyl groups on
the aliphatic chain was expected to further improve the efficiency
of the cyclization reaction (by virtue of the Thorpe-Ingold effect[19]).
However, this modification led to a significant decrease in both
the yield and TONs for formation of oxazolidine product 7b (Table
2, entry 2). Steric hindrance introduced by the two methyl groups
apparently has a larger effect on the reactivity than pre-
organization for cyclization when using substrate 7a. The reaction
did however proceed cleanly, as only product 7b and starting
material 7a were observed upon analysis of the crude reaction
mixture. Substitution of oxygen for an NH functionality in the
aliphatic chain resulted in a small decrease in the product yield
using [Co(TMP)] complex 3 as the catalyst (69% yield, TON = 17;
entry 3). In this reaction [Co(TPP)] complex 1 produced
imidazolidine product 8b in a comparable yield (67%, TON = 17).
In all reactions involving a secondary –NH group in the substrate
(entries 3-10) we used 2.4 equivalents of Boc2O to protect both
nitrogen atoms.
Some conversion could, however, be observed when high
catalyst loadings were used (see supporting information). In the
presence of di-tert-butyl dicarbonate (Boc2O) we observed the
desired Boc-protected cyclic amine product 5b (tert-butyl 2-
1
phenylpyrrolidine-1-carboxylate) by H-NMR spectroscopy. The
product was isolated in 17% yield (Table 1, entry 2, turnover
number (TON) = 17) after 16 hours of reaction. We were pleased
to see that under these conditions the TONs obtained with
[Co(TPP)] catalyst 1 in the conversion of substrate 5a to product
5b are already higher than those of most previously reported
homogeneous catalysts for this reaction.[13-15]
We continued our optimization by changing the catalyst; with
cobalt(II)
tetra(pentafluorophenyl)-porphyrin
([Co(TPF20P)]
complex 2, Figure 2) as the catalyst only trace amounts of the
desired product 5b (<5%) were obtained (Table 1, entry 3).
[Co(salophen)] complex 4 (Figure 2)[18] proved to be completely
inactive (entry 7). In contrast, marked improvements both in yield
and TON were observed using the electron-donating porphyrin
Table 2. Catalytic formation of oxazolidines and imidazolidines.[a]
tetra(2,4,6-trimethylphenyl)-porphyrin
complex
3 ([Co(TMP)], Figure 2) as the catalyst. The desired
product 5b was obtained in 36% isolated yield using 1
mol% of catalyst (TON = 35; Table 1, entry 4) at 38%
conversion of the substrate. No significant change in the
isolated product yield was observed upon changing the
solvent to benzene (entry 5). To our surprise, the presence
of up to 3 volume percent of water in the solvent mixture
did not result in a significant decrease in activity (entry 6),
which is quite remarkable as previously reported catalysts
are all very sensitive to the presence of even trace
amounts of water.
Isolated
Yield
Entry
Substrate
Product
TON
23
1
93%
6a
6b
2
8
32%
7a
8a
7b
8b
To verify whether the cobalt porphyrin complex is an active
component in the catalysis or merely initiating a metal-free
69%[b]
67%[c]
17[b]
17[c]
3
4
radical
reaction,
we
replaced
cobalt(II)
by
azobisisobutyributrile (AIBN, entry 8). However, using this
well-known radical initiator did not lead to any product
formation. At the low cobalt catalyst loadings used so far,
incomplete conversion of the azide 5a is observed after 16
hours, which nicely allows for proper comparison of the
TONs of the different catalysts (Table 1, entries 1-7). To
obtain synthetically useful yields of the desired product 5b
within the same reaction time, however, higher catalyst
loadings were used. With 2 and 4 mol% of [Co(TMP)]
catalyst 3, the product yield increased to 54% and 89%,
respectively (Table 1, entries 9 and 10). Importantly, none
of these reactions produced any significant amounts of
undesired linear (Boc-protected) amine products
previously observed for related systems.[13,15]
16[b]
69%[b]
8c
8b
5 [b,c]
6 [b,c]
7 [b,c]
8 [b,c]
9 [b,c]
10 [b,c]
R = Me, 9a
R = Ph, 10a
R = F, 11a
R = Cl, 12a
R = Br, 13a
R = OMe, 14a
R = Me, 9b
R = Ph, 10b
R = F, 11b
R = Cl, 12b
R = Br, 13b
R = OMe, 14b
96%
91%
84%
87%
95%
82%
24
22
21
22
24
20
Next we explored the substrate scope by examining the
synthesis of oxazolidines and imidazolidines using the
above [Co(por)]-catalyzed ring-closing CH bond
amination protocol. By introducing an oxygen atom in the
[a] Conditions: Substrate (0.3 mmol), Boc2O (1.2 equivalent), [Co(TMP)] (4 mol%), and
toluene (3.0 mL) were added and reacted for 16 h at 100 °C. At the end of the reaction
only starting material and products were observed. [b] 2.4 equivalents of Boc2O were
added. In entries 3 and 5-10, full conversion of the starting material was always
observed. The only observed side product was the corresponding azide with a Boc-
protected secondary nitrogen (compound 8c and compounds S6-S11, see Supporting
Information). [c] Commercially available [Co(TPP)] 1 was used as the catalyst.
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The decrease in yield could be due to the increased bulk of
the substrate after Boc-protection of the secondary amine.
This also explains why the difference in activity between the
two catalysts 1 and 3 is small for this substrate. When
substrate 8a was treated with Boc2O to yield substrate 8c
prior to the cyclization reaction no change in the product
yield was observed as compared to the one pot procedure
(Table 2, entry 4). We further decided to investigate the
tolerance of the reaction for substitution on the phenyl ring
of the amine containing substrates (Table 2, entries 5-10).
Because of the small difference in activity between
[Co(TPP)] (1) and [Co(TMP)] (3) for substrate 8a, the
commercially available [Co(TPP)] catalyst 1 was used for
substrates 9a-14a. In these cases we also used 2.4
equivalents of Boc2O in the reaction (Table 2, entry 5-10) to
prevent product inhibition. Using a 4 mol% catalyst loading,
high yields (up to 96%) were obtained for all substrates
containing a substituent on the para position of the phenyl
ring. The effect of electron-donating and electron-
withdrawing substituents is marginal, and in agreement with
the kinetic and computational studies described below,
which show that azide activation is rate limiting. At the end
of the reaction we always observed full conversion of the starting
material for substrates 8a-14a. The only observed side product in
these reactions was the corresponding Boc-protected azide
(compound 8c and compounds S6-S11, see Supporting
Information), again without formation of any significant amounts
of undesired linear (Boc protected) amines from the azide
substrates.[13,15]
Scheme 1. Application of the [Co(por)]-mediated intramolecular CH bond
amination ring-closing protocol for the synthesis of alternative heterocycles 15b-
18b.
Full conversion was observed after 16 h using 2 mol% catalyst
loading to yield the desired product 16b in 93% isolated yield
(TON = 45). Apparently, the increased stabilization of the benzylic
radical
is
sufficient
to
avoid
the
competitive
oligomerization/polymerization reactions observed for substrate
15a. Finally, a six-membered heterocycle 17b was found to be
accessible using substrate 17a, albeit in only 28% yield (TON =
7). As observed for substrate 15a, but in contrast to all other
reactions described above, 37% of the corresponding linear Boc-
protected amine product 17c and some ill-defined
oligomers/polymers were obtained as side products in this case.
In addition, activation of the allylic CH bond of substrate 18a
yields the six-membered heterocycle product 18b (38%, TON =
10). Other compounds detected in the reaction mixture were the
starting material 18a (37%), linear product 18c (12%) and small
amounts of unidentified products. Additional substrates used in
the CH amination protocol, varying in the BDE of the reacting
CH bond, are described in the supporting information (Table S1).
The results obtained with these substrates indicate that
intermolecular HAT starts to compete with intramolecular HAT
when the barrier for CH bond activation at the targeted position
for ring closing amination becomes too strong (i.e. higher BDEs
of the targeted CH bond and/or formation of six-membered rings
instead of five-membered rings). Substrates with weaker benzylic
CH bonds at the delta position react selectively to five-
membered N-heterocylic rings without any indication for
competing intermolecular HAT reactions (see Table 1 and
Table 2).
To further explore the scope of the cobalt porphyrin catalyst for
the preparation of N-saturated heterocycles from alkyl azide
fragments, we examined the azide containing disubstituted
arenes 15a-17a to obtain bicyclic isoindoline and
tetrahydroisoquinoline derivatives (Scheme 1). The presence of
the phenyl ring resulted in a decrease in the selectivity, as
isoindoline product 15b was obtained in only 27% yield. However,
full conversion of the substrate was observed. The protected
linear amine product 15c (35%) and some ill-defined
oligomeric/polymeric side products were observed as side
products (see Supporting Information). It seems that if the desired
ring-closing step requires breaking of a stronger CH bond
(higher BDE), the reaction is partially driven to intermolecular HAT
reactions (most likely from the alpha position of another azide
substrate), producing undesired side products. This is consistent
with the formation of oligomeric/polymeric products, linear Boc
protected amines as well as nitriles from substrates containing
even stronger CH bonds (see Supporting Information).
It is worth mentioning that substrate 16a reacts again selectively
to the N-heterocylic ring product 16b, which is supportive of a
relation between the BDE of the reacting CH bond and the ease
and selectivity of the ring-closing step. Note that replacing the
methyl group in 15a by an ethyl group (substrate 16a) lowers the
BDE of the reacting CH bond.
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data point to a pre-equilibrium involving weak and reversible
binding of azide 5a to [Co(TMP)] catalyst 3, followed by rate
limiting substrate activation involving dinitrogen loss from the
coordinated azide. Subsequent CH activation leading to CN
bond formation and ring closure is faster, but not barrierless (see
also the proposed mechanism in Scheme 3).
Mechanistic investigations
Kinetic studies
The mechanism of the intramolecular ring-closing CH bond
amination reaction was explored experimentally by kinetic
analysis of the reaction progress monitoring the conversion of
(4-azidobutyl)benzene substrate 5a into tert-butyl 2-
phenylpyrrolidine-1-carboxylate product 5b, using [Co(TMP)]
catalyst 3 in the presence of Boc2O. Following the reaction in time
(see Supporting Information) revealed clean first order kinetics in
both the [substrate] and the [catalyst], but zero order kinetics in
[Boc2O]. No substrate saturation effects were detected over a
broad concentration range of azide 5a. This translates into the
following empirical rate equation, with second order rate constant
k = 12 M-1 h-1:
The reaction rate was further evaluated at various temperatures
(80-115 °C) to obtain the activation parameters from the
Arrhenius and Eyring equations (see Supporting Information for
details). This led to the following experimental values: Ea = +18.7
 2.3 kcal mol-1, ΔG‡= +26.2  4.6 kcal mol-1, ΔH‡= +18.0  2.3
kcal mol-1 and ΔS‡= 22.0  6.2 cal mol-1 K-1. The rather large
negative activation entropy (22.0  6.2 e.u.) points to an ordered,
associative transition state, suggestive of an uphill substrate
binding event preceding rate limiting azide activation (see
proposed mechanism in Scheme 3). When the reaction was
performed in presence of TEMPO as a radical trap, a large
decrease in the turnover number of catalyst 2 was observed (with
5 eq TEMPO, TON = 9; with 25 eq TEMPO, TON = 3), in good
agreement with the proposed radical mechanism (Scheme 3).
Rate = -d[substrate]/dt = k[substrate 5a][catalyst 3]
To exclude the alternative possibility of a rate limiting CH bond
activation step we performed an inter- and intramolecular kinetic
isotope competition experiment using the bis-deuterated (d2-5a)
and
mono-deuterated
(d1-5a)
analogues
of
(4-
azidobutyl)benzene substrate 5a, respectively (see Scheme 2).
[a] Free energies (ΔG°373K in kcal mol-1), all energies (also TS1, TS2 and TS3)
relative to A.
Scheme 2. Intermolecular kinetic isotope competition experiment between non-
deuterated (4-azidobutyl)benzene substrate 5a and its bis-deuterated analogue
d2-5a (top) and intramolecular kinetic isotope competition experiment using
mono-deuterated substrate d1-5a (bottom).
[b] L = □ = vacant site (5-coordinate pathway).
[c] L = 5c (6-coordinate pathway).
Scheme 3. Proposed mechanism for [Co(por)] catalysed intramolecular CH
bond amination ring-closing reaction of 5a to 6b and the corresponding DFT
computed energies (BP86, def2-TZVP, disp3).[a]
In the intermolecular competition experiment (Scheme 2, top) no
kinetic isotope effect (KIE = 1) was observed, thus showing that
the CH bond activation step occurs after the rate limiting azide
activation step.[20] The intramolecular kinetic isotope competition
experiment (Scheme 2, bottom) does reveal a substantial kinetic
isotope effect (KIE = 7), showing that the CH activation step is in
itself not barrierless (see also Scheme 3). The rather large
intramolecular KIE is perhaps suggestive of some tunnelling
contribution to the CH activation step (see computational
mechanistic studies), as can be expected for a radical-type
hydrogen atom transfer (HAT) process.[21,22] Hence, the kinetic
Because product inhibition was observed in the reaction without
Boc2O we determined the association constant for
2-phenylpyrrolidine (5c) binding to the [Co(TMP)] catalyst 3. The
equilibrium constant for the formation of five-coordinate complex
[Co(TMP)(5c)] from [Co(TMP)] and 5c at r.t. was found to be K1 =
1300, while binding of a second molecule 5c to [Co(TMP)(5c)] to
form six-coordinate complex [Co(TMP)(5c)2] has a very low
equilibrium constant of K2 = 80 (see Supporting Information). We
were unable to determine the binding constant for (4-
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azidobutyl)benzene coordination to 3 because the equilibrium is
shifted towards the starting materials. This has previously also
been observed for aromatic azide substrates.[22] Assuming that
substrate binding and activation requires the free four-coordinate
[Co(TMP)] catalyst, and thus competes with product binding, the
considerable binding constant K1 associated with formation of the
product adduct [Co(TMP)(5c)] should indeed result in a significant
additional energy penalty to the rate limiting step (also at 373 K)
when the reaction is performed in absence of Boc2O (see Scheme
3).
Computational mechanistic studies
Figure 3. Spin density plot of intermediate C present in Scheme 3.
The mechanism was further explored computationally (DFT,
BP86, def2-TZVP, disp3), using a simplified model of the catalyst
without substituents at the porphyrin ring (Scheme 3). Based on
the kinetic studies described above, we anticipated that the initial
steps of the mechanism involve coordination of the aliphatic azide
5a to cobalt(II), followed by dinitrogen loss to produce a nitrene-
radical intermediate. Rate limiting azide activation has also been
proposed in the mechanisms for [Co(por)]-catalysed CH bond
amination reactions using activated azides (carbonazidates
[ROC(O)N3] or sulfonyl azides [RSO2N3]).[5,11,16] This indeed is a
plausible pathway according to the DFT calculations (Scheme 3;
for more details see Supporting Information). Azide coordination
is slightly endergonic (+3.2 kcal mol-1) and subsequent loss of
dinitrogen from intermediate B via TS1 to produce the key nitrene-
radical species C is also the rate limiting step in the computed
mechanism, in good agreement with the experimental kinetic
studies (vide supra).
While the predicted KIE calculated as such is in good qualitative
agreement with the experiments, the experimental value is larger
(KIE = 7). This is suggestive of some tunnelling contribution to the
CH bond splitting process, as can be expected for a radical-type
HAT process.[21,22] In good agreement with the experimental data
dissociation of amine product 5c from cobalt(II) species E is
endergonic, thus resulting in product inhibition (i.e. slower
reactions) in absence of Boc2O (see ESI for more DFT details).
Attack of Boc2O on radical intermediate D prior to radical rebound
cannot be fully excluded on the basis of the available
experimental data. However, in view of the very low computed
barrier for the radical rebound step (< 2 kcal mol-1) this pathway
seems unlikely.
Additional catalytic experiments based on the mechanistic
insights gathered
The computations further show a lower barrier for the rate-limiting
azide activation step along the five-coordinate pathway (ΔG‡=
+24.5 kcal mol-1; L = □ in Scheme 3) than along the six-coordinate
pathway with an additional molecule of product 5c bound to cobalt
as an axial ligand (ΔG‡= +28.5 kcal mol-1; L = 5c in Scheme 3).
This is in agreement with the experimentally observed inhibiting
effect of the unprotected amine product 5c on the reaction rates
of catalytic reactions performed in absence of Boc2O. The
computed activation parameters for TS1 (ΔG‡= +24.5 kcal mol-1,
ΔH‡= +16.3 kcal mol-1, ΔS‡= 21.9 e.u.) are in excellent
agreement with the experimental values determined from the
Arrhenius and Eyring equations (Ea = +18.7  2.3 kcal mol-1, ΔG‡=
+26.2  4.6 kcal mol-1, ΔH‡= +18.0  2.3 kcal mol-1 and ΔS‡= 22.0
 6.2 e.u.). A spin density plot of five-coordinate species C (Figure
3) shows 88% spin population at the nitrene moiety and only 6%
at Co, thus confirming the nitrene-radical nature of this key-
intermediate (see also Scheme 3).[16] HAT from the benzylic
position of the activated substrate to the nitrene-radical moiety
(TS2) to produce amido-benzyl radical intermediate D and the
subsequent radical rebound step (TS3) both have remarkably low
barriers. From the relative barriers of hydrogen and deuterium
abstraction in the HAT step a KIE = 3.4 was calculated. Such
calculations neglect any tunnelling effects, as they take only
differences in zero point energy (ZPE) into account, resulting from
isotope exchange in the vibrational analysis.
The mechanistic information gathered above called for some
additional experimental studies. First of all, binding of unprotected
product 5c to the catalyst is substantial, but the magnitude of the
experimentally determined binding constant (K1= 1300) suggests
that the activation barrier of the rate limiting azide activation step
in absence of Boc2O is raised only to a limited amount, and thus
it should be possible to overcome this increased barrier at higher
temperatures. As such, we argued that it might be possible to
obtain the unprotected cyclic amine 5c by conversion of substrate
5a without Boc2O at elevated temperature. Indeed, full conversion
of substrate 5a was observed when performing the catalytic
reaction with 4 mol% of [Co(TMP)] catalyst 3 at 140 °C in
chlorobenzene. As expected, the desired 2-phenylpyrrolidine 5c
was indeed formed, albeit in a low yield (19%, TON = 5). Several
undesired and unidentified side products were formed under
these non-optimized reaction conditions (see Supporting
Information).
In marked contrast to the reaction performed at 140 °C in absence
of Boc2O, the catalytic reactions (and kinetic studies) performed
in the presence of Boc2O allowed clean conversion of azide 5a to
the Boc-protected cyclic amine 5b at lower reaction temperatures
(80-115 °C). Combined with clean first order kinetics in both the
[catalyst] and the [azide substrate], the data suggest that catalyst
deactivation processes are minor and slow. As such we wondered
if higher TONs would be attainable when performing the reaction
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10.1002/chem.201700358
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at lower catalyst loading but at the same time higher absolute
concentration of both the substrate and the catalyst. Such
conditions are expected to shift the pre-equilibrium for substrate
binding somewhat further in the direction of the coordinated
complex B (Scheme 3), and at the same time may reduce any
detrimental effects of impurities in the solvent. This indeed leads
to higher TONs. Performing the reaction at a high substrate
concentration of 0.44 M, using 1 mol% of [Co(TMP)] catalyst 3,
led to formation of product 5b in 58% yield (TON = 59) after 16 h,
and the yield further increased to 73% (TON = 76) after 72 h of
reaction. These are the highest TONs for the cyclization of
substrate 5a reported to date.
This clearly calls for additional screening of chiral catalysts for
these types of reactions in follow-up studies. Perhaps most
importantly, the result strongly suggests that the reaction does not
proceed via formation of free nitrenes in a metal-free CH bond
activation pathway. This is an important observation, as in some
Fe and Ru catalysed nitrene transfer reactions formation of free
nitrenes (reacting outside the coordination sphere of the metal in
an uncontrolled manner) has been observed.[17] The observed
chirality transfer thus holds important additional mechanistic
information, and shows unambiguously that the CH bond
activation and CN bond formation steps in the overall catalytic
ring-closing reaction occur within the coordination sphere of
cobalt.
Enantioselective intramolecular ring-closing CH bond
amination
Conclusions
In the proposed reaction mechanism shown in Scheme 3 the
substrate remains coordinated to the cobalt centre throughout the
catalytic cycle. If correct, this should allow for enantioselective
reactions when using a chiral cobalt porphyrin catalyst. We
therefore performed the ring-closing CH bond amination reaction
of substrate 5a with a new chiral cobalt porphyrin catalyst
equipped with four (1S)-()-camphanic-ester substituents (19,
Figure 4).
A cobalt catalysed ring-closing CH amination protocol was
developed for the synthesis of
a variety of saturated
N-heterocycles. The applied air and moisture stable [Co(por)]
catalysts give significantly higher turnover numbers (up to 76)
than other reported homogeneous catalyst systems based on Fe
and Pd for these type of reactions. The use of di-tert-butyl
dicarbonate (Boc2O) prevents competitive binding of the formed
amine product, thereby significantly enhancing the reaction rate.
Detailed kinetic studies, kinetic isotope competition experiments
and supporting DFT calculations reveal a metallo-radical-type
mechanism involving rate limiting azide activation to form the key
cobalt(III)-nitrene radical intermediate. Subsequent low barrier
intramolecular HAT from a benzylic CH bond to the nitrene-
radical intermediate followed by a radical rebound step leads to
formation of the desired N-heterocyclic ring products. Kinetic
isotope competition experiments are in agreement with a radical-
type CH bond activation step (intramolecular KIE = 7), which
occurs after rate limiting azide activation (intermolecular KIE = 1).
Enantioselective ring-closing amination proved possible when
using a new chiral cobalt porphyrin catalyst equipped with four
(1S)-()-camphanic-ester substituents in the second coordination
sphere. Modest enantioselectivities (up to 46% ee) were achieved
in the ring closure of (4-azidobutyl)benzene, despite the high
reaction temperature used (80 C). This demonstrates for the first
time the feasibility of enantioselective radical-type ring closure of
aliphatic azides using metallo-radical catalysis,[23] and strongly
suggests that the CH bond activation and CN bond formation
steps of the overall catalytic ring-closing reaction occur in the
coordination sphere of cobalt. The involvement of free nitrenes in
these reactions seems unlikely. The ring closing amination
reactions described in this paper are rare examples of selective
catalytic transformations proceeding via one-electron substrate
activation steps producing discrete metal-bound nitrogen-centred
radical intermediates.[24] We hope that the prospects and
mechanistic information provided in this paper will guide others
and stimulate further research in this field. Experimental Section
Figure 4. Structure of (1S)-(-)-camphanic acid based chiral catalyst 19
(4 mol%) used in the enantioselective ring-closing CH bond amination reaction of
substrate 5a.
Synthesis and characterization of the new catalyst 19 is described
in the Supporting Information. The chiral catalyst 19 produces
product 5b in lower yields (33% yield, TON = 8, at 4 mol% catalyst
loading) compared to [Co(TMP)] catalyst 3, but indeed allowed
enantioselective product formation in 29% enantiomeric excess
(ee) at 100 °C (enantiomeric ratio 35:65). The ee increased to
46% (enantiomeric ratio 27:73) by lowering the reaction
temperature to 80 °C, although at a somewhat reduced product
yield (22%, TON = 6). Chirality transfer at these rather high
reaction temperatures is quite remarkable, and the results
demonstrate for the first time the feasibility of enantioselective
radical-type ring closure reactions from aliphatic azides using
metallo-radical catalysis (Figure 4).[23]
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10.1002/chem.201700358
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Driver, Angew. Chem. Int. Ed. 2014, 53, 785-788. c) Q. Nguyen, T.
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Experimental Section
General intramolecular CH bond amination procedure
To a dry Schlenk flask was added catalyst (12 µmol), substrate
(0.30 mmol) and di-tert-butyldicarbonate (0.36 mmol) in dry
toluene (3.0 mL). The stirred reaction mixture was heated to
100 °C for 16 h. After cooling to room temperature the crude
mixture was purified by flash chromatography (SiO2,
DCM/hexanes/TEA 50:50:1).
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Keywords: Cobalt Porphyrin • N-Heterocycles • Catalytic
Radical-type Reactions • Ring closing Reactions •
Enantioselective C−H bond Amination
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Entry for the Table of Contents
Layout 2:
FULL PAPER
Cobalt catalysed activation of
aliphatic azides enables the
direct synthesis of various
heterocycles from aliphatic
azides in good to excellent
yields. Detailed mechanistic
investigations reveal a
P. F. Kuijpers, M.J. Tiekink, W.B.
Breukelaar, D. L. J. Broere, N.P. van
Leest, J. I. van der Vlugt, J. N. H. Reek
and B. de Bruin*
Page No. – Page No.
metalloradical intramolecular
CH activation mechanism.
Enantioselective radical-type
ring closure CH amination
from aliphatic azides proved
possible.
Nitrene-radical approach to Saturated
Heterocycles;
Catalysed
Cobalt
Intramolecular
Porphyrin
Ring-
Closing CH Amination of Aliphatic
Azides
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