N-Heterocyclic Carbene Iron(III) Porphyrin-Catalyzed Intramolecular C(sp3)–H Amination of Alkyl Azides

Article abstract of DOI:10.1002/anie.201806059

Metal-catalyzed intramolecular C?H amination of alkyl azides constitutes an appealing approach to alicyclic amines; challenges remain in broadening substrate scope, enhancing regioselectivity, and applying the method to natural product synthesis. Herein we report an iron(III) porphyrin bearing axial N-heterocyclic carbene ligands which catalyzes the intramolecular C(sp³)–H amination of a wide variety of alkyl azides under microwave-assisted and thermal conditions, resulting in selective amination of tertiary, benzylic, allylic, secondary, and primary C?H bonds with up to 95 % yield. 14 out of 17 substrates were cyclized selectively at C4 to give pyrrolidines. The regioselectivity at C4 or C5 could be tuned by modifying the reactivity of the C5–H bond. Mechanistic studies revealed a concerted or a fast re-bound mechanism for the amination reaction. The reaction has been applied to the syntheses of tropane, nicotine, cis-octahydroindole, and leelamine derivatives.

Full text of DOI:10.1002/anie.201806059

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Accepted Article
Title: N-Heterocyclic Carbene Iron(III) Porphyrin-Catalyzed
Intramolecular C(sp³)-H Amination of Alkyl Azides
Authors: Ka-Pan Shing, Yungen Liu, Bei Cao, Xiao-Yong Chang,
Tingjie You, and Chi-Ming Che
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201806059
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10.1002/anie.201806059
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N-Heterocyclic Carbene Iron(III) Porphyrin-Catalyzed Intramolecular
C(sp3)H Amination of Alkyl Azides
Ka-Pan Shing, Yungen Liu, Bei Cao, Xiao-Yong Chang, Tingjie You, and Chi-Ming Che*
Abstract: Metal-catalyzed intramolecular C-H amination of alkyl azides
constitutes an appealing approach to alicyclic amines; challenges remain in
broadening substrate scope, enhancing regioselectivity and applying to natural
product synthesis. Herein we report an iron(III) porphyrin bearing axial N-
heterocyclic carbene ligands which catalyzes intramolecular C(sp3)-H
amination of a wide variety of alkyl azides under microwave-assisted and
thermal conditions, resulting in selective amination of tertiary, benzylic, allylic,
secondary, and primary C-H bonds with up to 95% yield. 14 out of 17
substrates were cyclized selectively at C4 to give pyrrolidines. The
regioselectivity at C4 or C5 could be tuned by modifying the C5-H reactivity.
Mechanistic studies revealed a concerted or a fast re-bound mechanism for
the amination reaction. The reaction has been applied to syntheses of tropane,
nicotine, cis-octahydroindoleand leelaminederivatives.
Alicyclic amines are ubiquitous in naturally-found and pharmaceutically
important molecules (Figure 1).[1] Development of metal-catalyzed
intramolecular C-H amination for syntheses of alicyclic amines from alkyl
azides (RN3) via metal-alkylnitrene (M=NR) intermediates is appealing,
as N2 is the sole by-product and diverse types of RN3 substrates are
available.[2] Such catalytic systems,[3,4] first reported by Betley and co-
workers using Fe-dipyrrinato catalysts (A, Figure 2) to produce
pyrrolidines from amination of 2 or 3 C(sp3)H bonds of C(sp3)-
Figure 2. Examples of iron-catalyzed intramolecular C(sp3)H amination of
alkyl azides. a) Developed by Betley and co-workers using Fe-dipyrrinato
azides in good-to-excellent product yields,[3a,d] are complementary to
other Fe-catalyzed C-H aminations of C(sp2)-azides.[5] It remains a
catalysts A. b) Described in this work using Fe-NHC porphyrin catalyst B.
challenge to develop an efficient catalytic system that exhibits broader
regioselectivity (e.g. cyclization at C5 to give piperidines without a vinyl
directing group), and is applicable to natural product synthesis. In this
regard, we turned our attention to Fe porphyrin catalysts, owing to the
analogy of C-H amination by heme Fe=NR species with C-H
hydroxylation by Fe-oxo species of cytochrome P450 enzymes.[3a] We
are particularly interested in developing Fe porphyrin catalysts bearing N-
heterocyclic carbene (NHC) axial ligand, in view of elevation of catalytic
efficiency of Ru(II) porphyrins by NHC axial ligand in carbene and aryl-
nitrene C-H insertion reactions.[6] Also, the oxo ligand of heme Fe-oxo
species bears oxyl radical character,[7] and for a Ru=O complex a strong
oxyl radical character of the oxo ligand trans to NHC ligand was
reported.[ 8 ] Previously we demonstrated microwave-accelerated iron
porphyrin-catalyzed intermolecular phosphoryl-, sulfonyl- or aryl-nitrene
transfer reactions.[9 ] Herein, we report the synthesis of an Fe-NHC
porphyrin, [FeIII(TDCPP)(IMe)2]I (B, Figure 2), which can efficiently
catalyze intramolecular amination of C-H bonds with a wide range of alkyl
azides under thermal and microwave-assisted conditions. This strategy
paves a way for facile conversion of alkyl azides to biologically and
medicinally important alkaloids including tropane and nornicotine and
also derivatives of cis-octahydroindoleandleelamine.
substrate scope (such as covering also 1 C-H bonds, pyridyl azides,
cyclic secondary azides and/or tertiary azides), shows high
Figure 1. Examples of alkaloids/amines.
[*]
K.-P. Shing, Dr. B. Cao, Dr. X.-Y. Chang, Prof. Dr. C.-M. Che
State Key Laboratory of Synthetic Chemistry
Department of Chemistry
The University of Hong Kong
Pokfulam Road, Hong Kong (China)
E-mail: cmche@hku.hk
Dr. Y. Liu, T. You
Department of Chemistry
South University of Science and Technology of China
Shenzhen, Guangdong 518055 (China)
ComplexBwas prepared byrefluxing[FeIII(TDCPP)]OTf with[HIMe]I
in DMF and characterized by ESI-MS, UV/Vis, 1H NMR (see Supporting
Information), and X-ray crystal structure determination (Figure 3; ruffled
conformation).[10] It is stable for up to several weeks towards air and
moisture in solid state and solution. The FeCNHC distances in B are
2.094(5) and 2.077(5) Å (CNHC-Fe-CNHC 179.7o), significantly longer than
FeCcarbene distances in [Fe(TPP)(CCl2)(OH2)] (1.83(3) Å)[11a] and [Fe(F20-
Prof. Dr. C.-M. Che
HKU Shenzhen Institute of Research and Innovation
Shenzhen 518053 (China)
Supporting information for this article is given via a link at the end of
the document.
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TPP)(CPh2)(MeIm)] (1.827(5) Å).[11b] Complex B exhibits paramagnetic
1H NMR signals (H: -0.99 ppm), and shows μeff of 1.63 μB (by Evans
method) indicating alow-spinFe(III) (S= 1/2) species.
was converted to pyrrolidine 8b and piperidine 8c in 56% combined yield
with 8c as the major product (8b/8c = 1:5), opposite to the preferential
formation of pyrrolidine 8b (8b/8c = 1.5:1; combined yield of 8b,c: 47%)
observed for A used in 100 mol%,[3a] indicating an unusual
regioselectivity of catalyst B. For 9a16a, their intramolecular CH
amination catalyzed by B also showed good-to-excellent product yields
and/or remarkable selectivity: (i) 9a (devoid of allylic, benzylic, and 3
CH bonds) resulted in a markedly higher C4-H (over C5-H) selectivity
than 7a and 8a, affording pyrrolidine 9b as the major product, together
with minor amount of piperidine 9c (9b/9c 5:1, entry 9). (ii) 10a (bearing a
pyridyl group) gave the pyridyl pyrrolidine 10b in 65% yield (entry 10;
using 10 mol% of [FeIII(TDCPP)Cl] showed no substrate conversion). (iii)
For 11a with an α-Ph group, a 90% yield of 11b (syn/anti 5:1) was
obtained (entry 11). Changing the α-Ph group to a benzyl group lowered
the catalytic activity and selectivity (cf. entries 11 and 12). (iv) 13a with 1
C4-H bonds and α-Ph group was cyclized to give pyrrolidine 1b in 50%
yield (entry 13). Remarkably, 14a bearing α-ester group, an inexpensive
chiral substrate prepared from D-leucine, underwent 1 C4-H amination
to give a proline-like product 14b in 85% yield (syn/anti 2:1, entry 14),
substantially higher than the 50% yield obtained for proline-like 2b (entry
2). In literature, a 17% isolated yield of pyrrolidine product was reported
for the intramolecular 1 C-H amination of CH3(CH2)2C(CH3)2N3
catalyzed by A (10 mol%).[3a] (v) 15a, an azido-cycloalkane, was
converted to a tropane product 15b in 63% yield (entry 15); the latter
bears a unique [3.2.1] bicyclic structure prevalent in a wide range of
naturally-found compounds such as alkaloids. (vi) Tertiary alkyl azide 16a
containing both C4-H and C5-H gave pyrrolidine 16b in 82% yield
(conversion: 95%) without piperidine product being observed (entry 16),
due possibly to enhancement of the five-membered ring selectivity by
Thrope-Ingold effect. These findings altogether contribute the first
example of metal-catalyzed intramolecular C-H amination of a tertiary
Figure 3. X-ray crystal structure of B (hydrogen atoms and counter-anion are
omitted) at 30% probability thermal ellipsoids. a) Top view. b) Side view.
Treatment of Ph(CH2)4N3 (1a), added via a syringe pump over 2
hours, with 20, 10, and 5 mol% of B at 115 C in toluene containing 1
equiv. of Boc2O, afforded pyrrolidine 1b in 77%, 74%, and 50% isolated
yield, respectively. Thus, 10 mol% of B was used in subsequent studies,
which covered a wide variety of alkyl azides 1a-16a (Table 1). The
intramolecular C-H amination of primary alkyl azides 9a and 10a (with the
latter bearing a pyridyl group), secondary alkyl azides 11a14a, cycloalkyl
azide 15a, andtertiary alkyl azide 16a have not been reported in previous
works.[3,4]
As shown in Table 1, B catalyzed intramolecular amination of
1a16a with product yields of up to 95%. The reactions of 1a6a gave
pyrrolidines in 74-95% yields (entries 1, 36), except for 2a (bearing
electron-withdrawing ester group) which gave pyrrolidine 2b in 50% yield
(entry 2). For 7a, a mixture of pyrrolidine 7b and piperidine 7c,
corresponding to amination at C4-H and C5-H, respectively, was
obtained in 50% combined yield with 7b/7c ratio of 1:1 (entry 7), similar to
the result obtained using 100 mol% of catalyst A.[3a] Using catalyst B, 8a
Thermal conditions: 10 mol% of B, alkyl azide (0.2 mmol, added via syringe pump within 5 h), Boc2O (0.2 mmol) and 4 Å molecular sieves (100 mg) in toluene under argon overnight. Microwave-
assisted conditions (results in square brackets): no molecular sieves, 140 oC under air (microwave power = 50 W) for 0.5 h, other conditions were the same except that azide was added in one-pot
manner. [a] Based on the crude 1H NMR spectrum with dimethyl fumarate as an internal standard. [b] isolated yield based on conversion for entries 1-6, 11-16 and 1H NMR yield for entries 7-10.
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10.1002/anie.201806059
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alkyl azide with high product yield. Previously, the reaction of
EtO2C(CH2)3C(CH3)2N3 catalyzed by A was reported to give the
pyrrolidineproduct in 11% yield.[3a]
The aminations of 3 (6a), benzylic (1a), allylic (4a), 2 (11a), and 1
(13a) C4-H bonds afforded pyrrolidines in yields of 93%, 74%, 75%,
cis-Octahydroindole core is prevalent in natural products such as
dysinosin A, a potent inhibitor of the blood coagulation cascade factor
VIIa.[13] We synthesized a substituted azidocycloalkane 17a (from a
common starting material (L)-menthol), which underwent B-catalyzed
intramolecular 1 C-H amination to give cis-octahydroindole 17b in 68%
90%, and 50% (Table 1), respectively, indicating areactivity order: 3 > 2, yield (>99% conversion, dr = 2:1) with excellent regioselectivity: only the
benzylic, allylic >> 1 C-H bond. Of substrates 1a-16a, 3a gave C4-H
amination product (2b) in the highest isolated yield of 95% (entry 3, Table
1), attributabletothe highreactivity of 3 C4-H bondcoupled with Thrope-
Ingold effect. The preferential formation of piperidine 8c from 8a (entry 8,
Table 1) reveals a reversal of regioselectivity by the presence of 3 C5-H
bond, different from the vinyl-directed C5-H amination of
CH2=CH(CH2)5N3 catalyzedby A.[3a]
1 C4-H bond at site ‘a’ was aminated whereas the 2 and 1 C4-H
bonds at sites ‘b’ and ‘c’, respectively, remain unreacted (Scheme 2).
Recycling catalyst B for this reaction led to nearly no drop in its activity
(Scheme 2). Under microwave-assisted conditions, the reaction showed
thesameregioselectivitygiving 17b in70% yield(Scheme 2).
We also examined the B-catalyzed intramolecular C-H amination
under microwave-assisted conditions; the results are depicted in Table 1
(see Supporting Information for optimization and control experiments).
The microwave reactions showed high tolerances with oxygen and
moistures, the reaction time was shortened (5 h  0.5 h), and the
product yields were improved (80-90% yields in 7 out of 10 entries)
compared with the results obtained under thermal conditions. For the
regioselectivity, the microwave-assisted conditions generally increased
the proportion of C4-H amination, as exemplified by entry 9 with 9b/9c
ratio of >20:1. These unprecedented results render this iron porphyrin-
NHC catalysis to be a simple, convenient and user-friendly method for
selective construction of C-N bonds from alkylazides.
Scheme 2. Synthesis of cis-octahydroindole 17band leelamine derivatives 18b and 18c.
To show the application in natural product synthesis, we have
developed a B-catalyzed C-H amination method, coupled with a facile N-
methylation after Boc-deprotection, for the synthesis of tropane 15c
(which contains a fused piperidine-pyrrolidine structure) via 15b, and
scaling up the C-H amination reaction by 3-fold afforded 15b in 70% yield
(Scheme 1). In addition, the cyclization of 15a catalyzed by B led to the
formation of a similar product 15b (76% isolated yield), which is an
important intermediate to the synthesis of cocaines.[12] This method was
further applied to the synthesis of a nicotine derivative, nornicotine (10c)
via 10b, with 10b obtained in 50% yield upon scaling up the reaction by
10-fold, giving a quantitative amount of 10c after treating 10b with
trifluoroacetic acid (Scheme 1). Under microwave-assisted conditions,
catalyst B was recycled for 5 consecutive runs using 15a as substrate
(Scheme 1); the isolated yield of 15b remained similar in the first three
runs (87%, 86%, 82%) and was still good or moderate in the 4th run
(70%) and 5th run (51%). Under the same conditions, catalyst
[FeIII(Por)Cl] (Por = F20-TPP, TDCPP)] afforded <10% yield of 15b even
inthefirst run.
The B-catalyzed CH amination method has also been applied to
modification of leelamine (Figure 1), a potent anti-melanoma agent.[14]
Upon treatment with imidazole-1-sulfonyl azide, leelamine was converted
to azide 18a, which underwent B-catalyzed cyclization to afford 18b in
78% isolated yield, followed by reaction with TFA to give 18c (Scheme 2).
To gain insight into the reaction mechanism, the effects of axial
ligand and radical clock/trap and also kinetic isotope effects (KIE) were
III
examined. [Fe (TDCPP)]OTf catalyzed the reaction of 3a to give 3b in
only 8% yield (Scheme 3a), in contrast to the 95% yield obtained for
catalyst B, revealing a vital role of the NHC axial ligand of B in the C-H
amination. DFT-calculations showed that without NHC ligand,
coordination of Fe3+ with alkyl azide seemingly requires breaking the
heme co-planarity with Fe3+ being out of the porphyrin plane (Figure
4b, 0.37 Å displacement), which is significantly endogonic (Figure S2,
ΔG = +10.73 kcal mol-1). However, the heme co-planarity of the Iron(III)
porphyrin is broken by the ruffled conformation engendered by ligation
with NHC, resulting in less significant displacement of Fe3+ upon
adduct formation with alkyl azide (Figure 4a, 0.15 Å). Such minimized
displacement accounts for the slight exergonicity in the formation of
Scheme 3. a) Effect of axial ligand in catalyst. b) Effect of radical clocks. c)
Scheme 1. Synthesis of tropane 15c and nornicotine 10c.
Effect of TEMPO. d) Kinetic isotope effect (KIE).
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(No. 2013CB834802) and the Basic Research Program of Shenzhen
(No. JCYJ20160229123546997, JCYJ20170412140251576 and
JCYJ20170818141858021).
Keywords: alkyl azides • C-H amination • iron • homogeneous
catalysis • porphyrinoids
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III
Figure 4. DFT-calculated geometric changes of a) [Fe (TDCPP)(NHC)]+ and b)
[Fe (TDCPP)]+ upon binding azide 1a (structures overlaid; Fe: orange, N: blue,
III
Cl: green).
Iron(III)-alkylazide adduct (Figure S2, ΔG = -1.83 kcal mol-1), which is
beneficial to subsequent decomposition and cyclization.
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We suggest that the catalytic cycle might be initiated by thermally
driven dissociation of one NHC ligand from B to give
[Fe(TDCPP)(NHC)]+ (observable by ESI-MS analysis), which binds an
alkyl azide to give [Fe(TDCPP)(NHC)(N3R)]+, with subsequent azide
decomposition and cyclization to afford cyclic amine (Figure S3). For
radical clock substrates 19a and 19a bearing cyclopropyl rings at C4, the
B-catalyzed reaction gave 19b and 19b in 55% and 50% yields,
respectively (Scheme 3b); no cyclopropyl ring-opened alkene product(s)
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1
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[4]
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concerted or very fast re-bound mechanism for the step of C-H
amination at C4. In the presence of TEMPO, the B-catalyzed reaction of
1a gave 1b in 15% yield, with amine byproduct 1c formed in 70% yield
(Scheme 3c); no radical-trapped species was observed. Possibly,
intramolecular radical re-bound between carbon and nitrogen is faster
than the intermolecular radical coupling with TEMPO. For the reaction of
PhC(D)H(CH2)3N3 (1a) catalyzed by B at 115 C, the KIE value based
on 1b′/1b ratio is 1.9 (Scheme 3d), markedly smaller than the KIE of 5.1
at 60 oCreportedfor catalyst A.[3a] Theseresults could also be ascribedto
C-H amination by a hydrogen abstraction mechanism with fast radical re-
bound or aconcerted-likemechanism.
In conclusion, a bis-NHC Fe(III)-porphyrin B has been synthesized,
which catalyzes intramolecular C-H amination of alkyl azides at 1, 2, 3,
benzylic and allylic C-H bonds with high selectivity and up to 95% product
yield under microwave-assisted/thermal conditions. The reactions
selectively gave pyrrolidines (amination at C4-H), except for the presence
of morereactive benzylic or 3 C5-H inwhichcases piperidines were also
formed. The B-catalyzed reaction has been applied to the synthesis of
nornicotine and cis-octahydroindole andleelaminederivatives andserves
as an appealing method of constructing structurally complex and
synthetic challengingtropanes (directlyfrom an azidocycloalkane).
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[10] CCDC 1570743 contains the supplementary crystallographic data for this
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Acknowledgements
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This work was supported by the State Key Laboratory of Synthetic
Chemistry, the Hong Kong Research Grants Council (HKU 17303815
and 17301817), the National Key Basic Research Program of China
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Entry for the Table of Contents
COMMUNICATION
Ka-Pan Shing, Yungen Liu, Bei Cao,
Xiao-Yong Chang, Tingjie You, and Chi-
Ming Che*
Page No. – Page No.
N-Heterocyclic Carbene Iron(III)
Porphyrin-Catalyzed Intramolecular
C(sp3)H Amination of Alkyl Azides
An iron(III) porphyrin N-heterocyclic carbene complex catalyzed intramolecular
C(sp3)-H amination of a wide variety of primary, secondary and tertiary alkyl azides
under microwave-assisted and thermal conditions resulting in selective amination of
tertiary, benzylic, allylic, secondary, and primary C-H bonds with up to 95% yield.
The reaction has been applied to syntheses of tropane, nicotine, cis-
octahydroindole and leelamine derivatives.
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