A Mild Cu(I)-Catalyzed Oxidative Aromatization of Indolines to Indoles

Article abstract of DOI:10.1021/acs.joc.6b01854

A novel method for the oxidation of indolines to indoles is described. The method uses a Cu(I) catalyst and an organic percarbonate as the stoichiometric oxidant. The procedure was successfully applied at 0.5 kg scale in the production of a key intermediate in the synthesis of Elbasvir, which is a novel therapy for the treatment of hepatitis C virus infection.

Full text of DOI:10.1021/acs.joc.6b01854

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Note
A Mild Cu(I)-Catalyzed Oxidative Aromatization of Indolines to Indoles
Feng Peng, Mark McLaughlin, Yizhou Liu, Ian Mangion, David M. Tschaen, and Yingju Xu
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b01854 • Publication Date (Web): 04 Oct 2016
Downloaded from http://pubs.acs.org on October 5, 2016
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A Mild Cu(I)-Catalyzed Oxidative Aromatization of Indolines to Indoles
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Feng Peng,* Mark McLaughlin,* Yizhou Liu, Ian Mangion, David M. Tschaen, Yingju Xu
Department of Process Chemistry, Merck & Co. Inc., Rahway, New Jersey 07065, United States
E-mail: feng.peng@merck.com; mark_mclaughlin@merck.com
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Abstract: A novel method for the oxidation of indolines to indoles using a Cu (I) catalyst and an
organic percarbonate as the stoichiometric oxidant is described. The method was successfully
applied to the production of 0.5 kg of a key intermediate with 92% yield, 99.9% ee in the
synthesis of Elbasvir, which is a novel therapy for the treatment of hepatitis C virus infection.
Indoles are pivotal substructures in many biologically significant natural products and
important medicines.1 One important method for the production of indoles is the
dehydrogenation of indolines. Although the literature contains many reports on the oxidation
of indolines to indoles,2 the development of “green” reaction conditions for this transformation
remains a valuable objective. Published procedures can involve the use of high reaction
temperatures or stoichiometric oxidants and sometimes deliver low yields of the desired indole
products together with large amounts of hazardous waste.2 In this regard, the development of
a catalytic and green indoline oxidation method would represent a useful contribution to the
area.3
Elbasvir (1) (Figure 1) is a component of Zepatier, a combination therapy recently
approved by the Food and Drug Adminstration (FDA) for the treatment of Hepatitis C virus (HCV)
infection.4 Merck Research Laboratories have disclosed several synthetic routes to Elbasvir, 5
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including one approach5a that requires oxidation of an indoline intermediate to indole.
Described herein are our efforts to develop a novel Cu-catalyzed method for this indoline
oxidation.6
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Figure 1. Structure of Elbasvir
A key synthetic challenge in the synthesis of Elbasvir is the construction of the
benzoxazinoindole, which contains a hemiaminal ether stereocenter. In one approach, this
problem was overcome by adoption of a stereochemical relay strategy, where the secondary
amine stereogenic center in indoline 2 was used to control the hemiaminal ether center via a
diastereoselective condensation with benzaldehyde to yield hemiaminal ether 3 (Scheme 1).5a
In order to regain the desired oxidation state for Elbasvir, it was necessary to oxidatively
aromatize intermediate 3, originally achieved by treatment with 1.6 eq. KMnO4.7 Although this
oxidation process can deliver indole 4 in high yield and purity without disruption of the carefully
established hemiaminal ether stereocenter (85% yield, >99.2% ee), the reaction generates large
amount of insoluble and hazardous MnO2 waste. Using this Elbasvir example as a test-case, we
sought to develop a new general method for the oxidation of sensitive indolines that maximizes
product yield and minimizes the environmental footprint of this commonly used synthetic
transformation (Scheme 1).
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Scheme 1. Current and Desired Approach toward the Benzoxazino-indole 4.
We initially conducted a broad screen of possible alternatives utilizing high-
throughput experimentation (HTE) technology.8 Following a survey of more than 50 reaction
conditions,9 it became clear that clean oxidation of the Elbasvir indoline intermediate 3 is non-
trivial; maintaining stereochemical integrity at the hemiaminal ether functional group is
particularly challenging.10 Indeed, the majority of conditions tested led to either poor
conversion, or significant over-oxidation of 4 to provide multiple side products/degradants, or
epimerization of the stereocenter. Notably, the use of tert-butylhydroperoxide (TBHP)11 as a
stoichiometric oxidant in conjunction with various metal catalysts emerged as one of the few
promising options (Table 1). From a green chemistry perspective, TBHP is more attractive than
KMnO4 because the stoichiometric by-products from this reagent are the relatively benign tert-
butanol and water. When these conditions were employed at 10 g scale, indole 4 was obtained
in 81% chemical yield with 99.6% ee, although the reaction required 72 h to reach completion
(Scheme 2).
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Scheme 2. Cu(OAc)2/TBHP Promoted Indoline Oxidation.
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Further optimization to improve the yield was hampered by the formation of by-product
5. Compound 5 was produced under all conditions using TBHP so we decided to investigate
other organic oxidants (Table 1) to determine if they could minimize by-product formation and
accelerate the desired reaction rate. Our selection of organic oxidants focused on those that
are economical and readily available; organic peresters met both of these critieria.
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It has been proposed that the combination of TBHP with Cu(OAc)2 generates tert-butoxy
radical,12 which we postulated as the key reactive species in this indoline oxidation. Similar to
TBHP, tert-butyl peresters are also reported to generate the tert-butoxy radical under certain
conditions.13 We envisaged that the weaker O-O bond in peresters (as compared with TBHP13)
could accelerate generation of the tert-butoxy radical, and potentially increase the reaction
rate. In addition, without a free OH in these peresters, the formation of side product 5 would
hopefully be suppressed.14
To quickly evaluate this hypothesis, we again leveraged HTE techniques. For the
selection of catalysts, our screening focused on non-precious metal catalysts, 15, 16 including Fe,
Cu, Co, Ni, Mn, all of which are well documented in the literature to promote redox reactions
via a single electron transfer pathway.17 While Fe, Co, Ni and Mn catalysts did not provide
useful results (entries 3-8), to our delight, we observed that the combination of peresters and
CuCl provided good conversion/%ee and avoided the formation of by-product 5.
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Table 1. Selected Screening Examples.
With tert-butyl peroxyacetate (TBPA) and tert-butyl peroxybenzoate (TBPB), we
isolated indole 4 with 88% ee and 86% ee respectively (Table 1, entries 9 and 10). Control
experiments subjecting indole 4 with 99% ee to the reaction conditions established that the
hemiaminal ether stereocenter in 4 is robust and does not lose stereochemical integrity.
Therefore, we suspected erosion of the starting material 3 during the reaction as the cause of
the lower %ee observed in the indole product 4. Further control experiments confirmed that 3
is indeed susceptible to epimerization under acidic conditions and the formation of acetic acid
or benzoic acid by-products from TBPA/TBPB could be the reason for the %ee values observed
in entries 9 and 10.18 With these observations in mind, we turned our attention to tert-
butylperoxy 2-ethylhexyl carbonate (TBPC), reasoning that the pH-neutral by-products (tert-
butanol and 2-ethylhexanol) would avoid stereochemical erosion of the starting indoline 3. This
hypothesis was supported when we observed this oxidant provided indole 4 with 99.8% ee
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using CuCl as catalyst. Using CuCl, it was difficult to further improve the reaction conversion
due to the low solubility of this catalyst in organic solvents. Therefore, we sought alternative,
potentially more soluble Cu(I) catalysts. Ultimately it was determined that
tetrakis(acetonitrile)copper tetrafluoroborate-[Cu(MeCN)4]BF4 promotes a very clean reaction
with good conversion and ee.19
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Having identified the optimal catalyst and oxidant, we then examined additional
reaction parameters. A significant solvent dependence of reaction rate, ee, and conversion was
observed, with MeCN being optimal among the common organic solvents studied.20 The
reaction can be carried out between 20 oC and 55 oC while maintaining high enantiomeric
excess in the product indole 4. We chose 35 oC as our preferred reaction temperature,
balancing stability of TBPC against reaction rate.21 At this temperature, we found that only 1.2
equiv. of TBPC is required to achieve full conversion of the indoline. The optimized process was
demonstrated using 0.5 kg of indoline 3 and provided indole 4 in 92% isolated yield, 99.9% LCAP
and 99.9% ee (Scheme 3). Importantly, indole 4 can be directly isolated via crystallization
following addition of water at completion of the reaction.
Scheme 3. 500 g Scale Elbasvir Indoline Oxidation Demostration.
With the optimized conditions defined, we sought to test the generality of this process
with respect to different indoline substrates. Using substituted indolines 6a-e (entries 1-5,
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Table 2), the desired indoles were obtained in good yields. Unsubstituted indoline 6f (entry 6,
Table 2) afforded the indole 7f in moderate yield.
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Table 2. Cu(I)-catalyzed indoline oxidation.
As demonstrated in the oxidation of our key substrate 3, a significant advantage of this
new method is its mild character, which maintains the stereochemical integrity of the sensitive
hemiaminal ether. When a range of substituted indolines bearing an enantiomerically pure
hemiaminal stereocenter were subjected to this condition, the desired indoles were obtained in
excellent yield and ee. (Table 3)
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Table 3. Cu(I)-catalyzed indoline oxidation with hemiaminal stereocenter.
To gain deeper insight into this new Cu(I)-catalyzed process, we conducted several
control experiments. It is known that the Cu(I) catalyst can be oxidized by organic peresters to
generate Cu(II) species.22, 23 However, when indoline 3 was subjected to a stoichiometric
amount of the Cu(II) catalyst [Cu(MeCN)4](BF4)224 in MeCN with K2CO3 as acid scavenger, we did
not observe any indole 4 (only starting material was recovered; without K2CO3, decomposition
of hemiaminal were observed since [Cu(MeCN)4](BF4)2 is a strong Lewis acid). When indoline 3
was subjected to [Cu(MeCN)4](BF4) in the absence of TBPC oxidant, we observed no product.
Likewise, treatment of indoline 3 with TBPC in the absence of catalyst resulted in no conversion.
These experiments suggest that the reactive species is thet-butoxy radical (asobserved by EPR
experiments25), generated upon mixing the Cu(I) catalyst with TBPC. This is consistent with
reports in the literature that Cu(I) can reduce peresters to form tert-butoxy radicals (the
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Kharasch-Sosnovsky Reaction22). Taking all of these observations into account, we propose the
Cu(I) catalyst undergoes a single electron transfer reaction with TBPC to provide the tert-butoxy
radical, which then reacts with 3 via hydrogen abstraction reaction (HAT)26 to give carbon
radical species 10.27 A Cu(II)-mediated Kochi type radical oxidation reaction28 could afford
iminium 11 and subsequent aromatization could deliver the desired indole 4. (Figure 2). To
establish the presence of radicals in the desired process, we ran the reaction with one equiv. of
BHT (radical inhibitor). This reaction provided mainly the recovered starting material, 29 which is
consistent with the mechanistic hypothesis.
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Figure 2. Proposed Mechanism
In summary, we utilized a blend of rational design and HTE experimentation to discover
a new, general procedure for indoline oxidation to indoles. The novel combination of catalytic
([Cu(MeCN)4]BF4) with a readily available organic perester oxidant (TBPC) cleanly aromatizes
indoline substrates to afford the desired indoles in good yield and with environmentally-
friendly byproducts. This new method was demonstrated across a variety of indolines, including
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some containing potentially sensitive chiral functional groups and good results were generally
observed. Moreover, the method was applied to the synthesis of the HCV drug Elbasvir,
resulting in smooth access to the key intermediate indole 4. Given the ease of operation, ready
availability of reagents and relative efficiency of this new oxidation process, we believe it will be
of significant utility to the synthetic organic chemistry community.
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Experimental Section
General Method Unless otherwise noted, all reactions were performed under a nitrogen
atmosphere. All reagents and solvents were commercially available and used without further
purification unless indicated otherwise. Yields reported are for isolated, spectroscopically pure
compounds. NMR spectra were recorded on 400 or 500 MHz instruments. The residual solvent
1
protons (1H) or the solvent carbons (13C) were used as internal standards. H NMR data are
presented as follows: chemical shift in ppm downfield from tetramethylsilane (multiplicity,
coupling constant, integration). The following abbreviations are used in reporting NMR data: s,
singlet; br s, broad singlet; d, doublet; t, triplet; q, quartet; qt, quartet of triplets; dd, doublet of
doublets; dt, doublet of triplets; AB, AB quartet; m, multiplet. High-resolution mass spectra
were recorded on Q-TOF spectrometer. HPLC condition for indole 4 (Xterra C8 150 x 4.6 mm,
3.5µm particle size ): A, water with 0.1% ammonium hydroxide, B, acetonitrile, gradient from
A:B 95:5 to A:B 15:85 in 20 mins, hold at A:B 15:85 for 5 mins. Run time 25 min, flow 1.2
o
ml/min, 20 C, 220 nm UV detector. Chiral HPLC condition for enantiomeric excess analysis of
compound 4, 9b, 9c and 9d (Chiralpak AS-RH, 150 x 4.6 mm, 5 um): A, water, B, acetonitrile,
gradient from A:B 25:75 to A:B 10:90 in 10 mins, hold at A:B 10:90 for 2 mins. Run time 12 min,
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flow 1.0 ml/min, 20 C, 346 nm UV detector. SFC condition for enantiomeric excess analysis of
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compound 9a (ChiralPak IA3- 150 mm x 4.6 mm): A, CO2, B, IPA, gradient from A:B 99:1 to A:B
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60:40 in 5 mins, hold at A:B 60:40 for 1 mins. Run time 6 min, flow 3.0 ml/min, 40 C, 210 nm
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UV detector. Indoline 8a to 8d were prepared according to a Merck procedure.7 Indoline 6a to
6c were prepared following Kikugawa’s procedure.30
(6S,12aR)-3,10-dibromo-6-pentyl-12,12a-dihydro-6H-benzo[5,6][1,3]oxazino[3,4-a]indole (8a):
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gray solid, 1.1g, 91% IY. mp 113-115 C. H NMR (400 MHz, CD3CN) δ 7.28 – 7.21 (m, 2H), 7.14
(dd, J = 8.3, 0.9 Hz, 1H), 7.09 (dd, J = 8.3, 1.9 Hz, 1H), 6.88 (d, J = 1.9 Hz, 1H), 6.83 (d, J = 8.3 Hz,
1H), 5.69 (t, J = 7.0 Hz, 1H), 5.05 (d, J = 8.8 Hz, 1H), 3.51 (ddt, J = 16.1, 8.9, 1.3 Hz, 1H), 3.19 (d, J
= 16.1 Hz, 1H), 1.90 (dt, J = 8.8, 6.6 Hz, 2H), 1.53 (td, J = 8.8, 7.8, 4.4 Hz, 2H), 1.40 – 1.29 (m, 4H),
0.95 – 0.86 (m, 3H); 13C NMR (101 MHz, DMSO-d6) δ 14.3, 22.5, 24.8, 31.2, 31.7, 36.1, 55.1,
83.4, 111.6, 112.2, 120.7, 123.9, 124.2, 128.4, 129.6, 130.2, 132.3, 148.7, 153.2; HRMS (ESI+):
calcd for C20H22Br2NO [M+H] 450.0068, found 450.0071.
(6S,12aR)-3,10-dibromo-6-(3-fluorophenyl)-12,12a-dihydro-6H-benzo[5,6][1,3]oxazino[3,4-
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a]indole (8b): white solid, 1.2g, 93% IY, mp 116-118 C 1H NMR (400 MHz, CD3CN) δ 7.46 –
7.39 (m, 2H), 7.38 – 7.27 (m, 3H), 7.14 (d, J = 1.9 Hz, 1H), 7.13 – 7.09 (m, 1H), 7.07 (dd, J = 8.3,
2.0 Hz, 1H), 7.03 – 7.00 (m, 1H), 7.00 – 6.97 (m, 1H), 6.91 (s, 1H), 4.77 (d, J = 8.9 Hz, 1H), 3.64 –
3.51 (m, 1H), 3.17 (d, J = 16.2 Hz, 1H); 13C NMR (101 MHz, DMSO-d6) δ 36.3, 55.5, 82.7, 112.2,
112.5, 113.9, 115.7, 115.9, 119.9, 120.8, 123.2, 124.1, 124.6, 124.7, 128.5, 129.6, 130.3, 131.4,
131.5, 132.4, 142.1, 141.3, 148.5, 153.2, 162.9 (d, 1JC-F = 244.1 Hz ); 19F NMR (470 MHz, DMSO-
d6): δ -111.97; HRMS (ESI+): calcd for C21H15Br2FNO [M+H] 473.9504, found 473.9500.
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(6S,12aR)-3,10-dibromo-6-(2,5-difluorophenyl)-12,12a-dihydro-6H-
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benzo[5,6][1,3]oxazino[3,4-a]indole (8c7): white solid, 1.25g, 92% IY. mp 171-173 C. H NMR
(400 MHz, CD3CN) δ 7.34 – 7.30 (m, 1H), 7.29 – 7.27 (m, 1H), 7.25 – 7.14 (m, 2H), 7.14 – 7.12
(m, 2H), 7.10 (dt, J = 8.2, 0.6 Hz, 1H), 7.08 – 7.03 (m, 2H), 7.00 (d, J = 8.4 Hz, 1H), 4.72 (d, J = 8.7
Hz, 1H), 3.49 (ddt, J = 16.2, 8.8, 1.3 Hz, 1H), 3.21 (d, J = 16.2 Hz, 1H). 13C NMR (125 MHz, DMSO-
d6): δ 35.9, 55.2, 79.3, 112.1, 112.1, 114.7, 114.7, 114.9, 115.0, 117.5, 117.6, 117.7, 117.8,
118.5, 118.6, 118.8, 118.9, 119.4, 124.1, 127.1, 127.2, 127.3, 127.4, 128.6, 129.5, 130.4, 132.1,
148.1, 153.4, 154.9, 154.9, 158.1 (d, 1JC-F = 240.6 Hz), 156.1 (d, 1JC-F = 245.4 Hz); 19F NMR (470
MHz, DMSO-d6): δ-119.94, -119.90, −117.81, −117.77; HRMS(ESI+): calcd for C21H14Br2F2NO
[M+H] 491.9410, found 491.9413.
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(6S,12aR)-3,10-dibromo-6-(tert-butyl)-12,12a-dihydro-6H-benzo[5,6][1,3]oxazino[3,4-a]indole
(8d): gray solid, 1.06 g, 90% IY. mp 107-109 oC. 1H NMR (400 MHz, CD3CN) δ 7.27 – 7.19 (m, 2H),
7.12 (dd, J = 8.3, 1.0 Hz, 1H), 7.06 (dd, J = 8.2, 2.0 Hz, 1H), 6.97 (d, J = 2.0 Hz, 1H), 6.72 (d, J = 8.2
Hz, 1H), 5.28 (d, J = 0.6 Hz, 1H), 5.16 – 5.08 (m, 1H), 3.59 – 3.48 (m, 1H), 3.35 – 3.26 (m, 1H),
1.11 (s, 8H). 13C NMR (101 MHz, DMSO-d6) δ 26.5, 35.7, 38.1, 55.9, 90.1, 110.8, 111.4, 118.8,
120.7, 123.5, 124.3, 128.1, 128.7, 130.2, 130.9, 150.3, 154.8; HRMS (ESI+): calcd for C19H20Br2NO
[M+H] 435.9912, found 435.9924.
Representative Experimental Procedure for Cu-catalyzed oxidative aromatization of indolines
to indoles using [Cu(MeCN)4](BF4) and tert-Butylperoxy 2-ethylhexyl carbonate (TBPC):
To a 10 mL round bottom flask with a magnetic stir bar were charged indoline (500 mg),
acetonitrile (1.5 mL) and [Cu(MeCN)4](BF4) (0.05 mol equiv to indoline) under nitrogen. The
reaction mixture was heated to 35 oC and charged with tert-Butylperoxy 2-ethylhexyl carbonate
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(TBPC, 1.2 mol equiv to indoline) dropwise. The reaction was aged at 35 oC until completion. For
reactions using indoling 6a to 6f, the reaction mixture was first quenched with 10% NaHSO3
solution, extracted with EtOAc, and concentrated down. The indole products 7a to 7f were
isolated by flash chromatography (silica gel,hexane /ethyl acetate). For reactions using indoline
8a to 8d, the indole 9a to 9d were isolated by simply filtrating the reaction mixture. The
isolated solid were washed with MeCN and dried under vacuum with nitrogen sweep.
(S)-3,10-dibromo-6-phenyl-6H-benzo[5,6][1,3]oxazino[3,4-a]indole (47): white solid, 467 g
(500 g scale reaction), 92% IY. 99.9% ee. mp 177-179 oC. 1H NMR (500 MHz, DMSO-d6): δ 7.83 (d;
J = 1.8 Hz; 1 H); 7.82 (t; J = 4.0 Hz; 2 H); 7.36 (d; J = 1.9 Hz; 1 H); 7.26–7.35 (m; 6 H); 7.17 (s; 1 H);
6.92–6.94 (m; 2 H); 13C NMR (125 MHz, DMSO-d6): δ 83.4, 98.1, 112.6, 113.8, 117.2, 121.4,
122.3, 123.5, 125.7, 126.4, 126.7, 126.7, 129.3, 130.1, 130.7, 131.8, 134.3, 137.1, 150.1; HRMS
(ESI+): calcd for C21H14Br2NO [M+H] 455.9417, found 455.9435. [α]25D = −113.6 (c = 1.0, CHCl3).
(6S,12aR)-3,10-dibromo-12a-(tert-butylperoxy)-6-phenyl-6H-benzo[5,6][1,3]oxazino[3,4-
a]indol-12(12aH)-one (5): isolated as yellow oil in the Cu(OAc)2/TBHP reaction by silica gel
column, 80 mg (1 g scale reaction), 8% IY. 1H NMR (600 MHz, CDCl3) δ 7.75 (s, 1H), 7.71-7.67 (m,
1H), 7.65-7.55 (m, 3H), 7.30 – 7.22 (m, 3H), 7.20-7.15 (m, 2H), 7.08-7.03 (m, 1H), 6.9 (s, 1H),
1.25 (s, 9H); 13C NMR (150 MHz, CDCl3): δ 26.7, 81.8, 83.6, 89.3, 113.8, 114.4, 114.7, 120.7,
123.8, 125.1, 125.8, 127.8, 127.9, 128.2, 128.7, 130.7, 135.7, 140.3, 152.4, 157.9, 193.6; HRMS
(ESP): calcd for C25H21Br2NNaO4 [M+Na] 579.974, found 579.976.
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1-cyclohexyl-1H-indole (7a31): colorless oil, 452 mg, 90% IY. 1H NMR (500 MHz, CDCl3) δ 7.72 –
7.67 (m, 1H), 7.45 (dd, J = 8.3, 1.0 Hz, 1H), 7.28 (d, J = 3.2 Hz, 1H), 7.26 (ddd, J = 8.2, 7.0, 1.2 Hz,
1H), 7.16 (ddd, J = 8.0, 7.0, 1.0 Hz, 1H), 6.57 (dd, J = 3.2, 0.8 Hz, 1H), 4.29 (tt, J = 11.9, 3.7 Hz,
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1H), 2.26 – 2.13 (m, 2H), 2.04 – 1.96 (m, 2H), 1.86 (ddt, J = 13.1, 3.4, 1.8 Hz, 1H), 1.82 – 1.72 (m,
2H), 1.57 (qt, J = 13.2, 3.5 Hz, 2H), 1.36 (qt, J = 13.6, 4.0 Hz, 1H); 13C NMR (126 MHz, CDCl3) δ
25.7, 26.0, 33.6, 55.1, 101.0, 109.4, 119.2, 121.0, 121.1, 124.0, 128.5, 135.6; HRMS (ESI+): calcd
for C14H18N [M+H] 200.1439, found 200.1449.
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1-cyclohexyl-3-methyl-1H-indole (7b32): isolated as oil, 427 mg, 85% yield. 1H NMR (400 MHz,
CDCl3) δ 7.65 (dt, J = 7.8, 1.0 Hz, 1H), 7.44 – 7.37 (m, 1H), 7.31 – 7.24 (m, 1H), 7.18 (ddd, J = 8.0,
7.0, 1.1 Hz, 1H), 7.07 (d, J = 1.1 Hz, 1H), 4.24 (ddt, J = 11.8, 7.5, 3.7 Hz, 1H), 2.42 (d, J = 1.1 Hz,
3H), 2.18 (ddt, J = 12.6, 3.9, 1.6 Hz, 2H), 2.06 – 1.96 (m, 2H), 1.87 (dtt, J = 11.4, 3.4, 1.7 Hz, 1H),
1.83 – 1.69 (m, 2H), 1.64 – 1.49 (m, 2H), 1.42 – 1.30 (m, 2H); 13C NMR (126 MHz, CDCl3) δ 9.8,
25.8, 26.1, 33.6, 54.9, 109.2, 110.1, 118.5, 119.0, 121.1, 121.8, 128.6, 135.9; HRMS (ESI+): calcd
for C15H20N [M+H] 214.1596, found 214.1606.
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1-cyclohexyl-2-methyl-1H-indole (7c33): isolated as pale yellow oil, 437 mg, 87% yield. H NMR
(400 MHz, CDCl3) δ 7.61 – 7.52 (m, 2H), 7.15 (ddd, J = 8.5, 7.0, 1.4 Hz, 1H), 7.09 (ddd, J = 7.9, 7.0,
1.1 Hz, 1H), 6.28 (t, J = 0.9 Hz, 1H), 4.22 (tt, J = 12.3, 3.9 Hz, 1H), 2.51 (d, J = 1.0 Hz, 3H), 2.33 (tt,
J = 12.7, 7.1 Hz, 2H), 2.08 – 1.92 (m, 5H), 1.91 – 1.79 (m, 1H), 1.61 – 1.30 (m, 4H); 13C NMR (101
MHz, CDCl3) δ 14.2, 25.6, 26.5, 31.5, 55.8, 100.5, 111.2, 118.7, 119.7, 119.9, 128.6, 135.6, 136.2;
HRMS (ESI+): calcd for C15H20N [M+H] 214.1596, found 214.1595.
1-benzyl-1H-indole (7d34): isolated as oil, 375 mg, 75% yield. 1H NMR (400 MHz, CDCl3) δ 7.71
(dt, J = 7.7, 1.0 Hz, 1H), 7.39 – 7.10 (m, 10H), 6.61 (dd, J = 3.1, 0.9 Hz, 1H), 5.37 (s, 2H); 13C NMR
(101 MHz, CDCl3) δ 50.1, 101.7, 109.7, 119.5, 121.0, 121.7, 126.8, 127.6, 128.3, 128.8, 136.3,
137.6; HRMS (ESI+): calcd for C15H14N [M+H] 208.1126, found 208.1133.
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(S)-3,10-dibromo-6-pentyl-6H-benzo[5,6][1,3]oxazino[3,4-a]indole (9a): white solid, 466 mg,
93% yield, 99.2% ee. mp 131-133 oC. 1H NMR (500 MHz, CDCl3) δ 7.77 (d, J = 1.9 Hz, 1H), 7.53 (d,
J = 8.6 Hz, 1H), 7.32 (dd, J = 8.7, 1.9 Hz, 1H), 7.30 – 7.22 (m, 2H), 7.14 (d, J = 8.6 Hz, 1H), 6.74 (s,
1H), 6.27 (dd, J = 8.7, 4.5 Hz, 1H), 1.95 (dtd, J = 14.3, 9.4, 5.1 Hz, 1H), 1.73 (td, J = 9.6, 5.0 Hz,
1H), 1.64 – 1.37 (m, 3H), 1.30 (dq, J = 7.6, 4.5, 3.6 Hz, 4H), 0.89 (d, J = 6.5 Hz, 3H); 13C NMR (126
MHz, CDCl3) δ 13.9, 22.4, 24.4, 31.1, 34.2, 84.2, 96.2, 110.2, 113.7, 116.8, 121.3, 122.4, 123.4,
125.1, 125.2, 126.1, 130.6, 133.0, 149.3; 19F NMR (470 MHz, DMSO-d6): δ -112.22; HRMS (ESI+):
calcd for C20H20Br2NO [M+H] 447.9911, found 447.9925.
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(S)-3,10-dibromo-6-(3-fluorophenyl)-6H-benzo[5,6][1,3]oxazino[3,4-a]indole (9b): white solid,
447 mg, 89% yield, 99.6% ee. mp 143-145 oC. 1H NMR (400 MHz, DMSO-d6) δ 7.89 (d, J = 1.8 Hz,
1H), 7.86 (s, 1H), 7.83 (d, J = 8.3 Hz, 1H), 7.43 (d, J = 1.9 Hz, 1H), 7.39 (d, J = 8.8 Hz, 1H), 7.37 –
7.26 (m, 3H), 7.18 (d, J = 8.0 Hz, 2H), 6.81 (dt, J = 9.7, 2.1 Hz, 1H), 6.63 (dt, J = 7.7, 0.9 Hz, 1H);
13C NMR (101 MHz, DMSO-d6) δ 82.6, 98.3, 112.6, 113.6, 113.8, 114.0, 116.9, 117.1, 117.2,
121.5, 122.4, 122.6, 123.5, 125.9, 126.5, 126.9, 130.6, 131.5, 131.6, 131.6, 134.2, 140.0, 149.7,
162.6 (d, 1JC-F = 245.4 Hz); HRMS (ESI+): calcd for C21H13Br2FNO [M+H] 471.9348, found
471.9343.
(S)-3,10-dibromo-6-(2,5-difluorophenyl)-6H-benzo[5,6][1,3]oxazino[3,4-a]indole ( 9c7): white
solid, 427 mg, 85% yield, 99.7% ee. mp 190-192 oC. 1H NMR (400 MHz, DMSO-d6): δ 8.02 (s; 1 H);
7.88–7.90 (m; 2 H); 7.38–7.46 (m; 2 H); 7.35 (dd; J = 8.28; 1.93 Hz; 1 H); 7.28–7.31 (m; 2 H); 7.25
(s; 1 H); 5.80 (ddd; J = 8.45; 5.51; 3.20 Hz; 1 H). 13C NMR (100 MHz, DMSO-d6): δ 79.3, 98.4,
112.8, 113.7, 113.8, 114.0, 114.0, 114.3, 116.8, 118.7, 118.8, 118.9, 119.0, 119.1, 119.2, 119.3,
119.4, 121.1, 122.5, 123.6, 125.6, 125.6, 125.7, 125.8, 126.0, 126.6, 127.2, 130.7, 131.8, 133.7,
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149.3, 156.5 (d, 1JC-F = 245.3 Hz), 158.5 (d, 1JC-F = 241.2 Hz); HRMS (ESI+): calcd for
C21H12Br2F2NO [M+H]489.9254, found 489.9246. [α]25D = −124.5 (c = 0.4, DMF)
(S)-3,10-dibromo-6-(tert-butyl)-6H-benzo[5,6][1,3]oxazino[3,4-a]indole (9d): white solid, 472
mg, 95% yield, 99.2% ee. 134-136 oC. 1H NMR (400 MHz, CDCl3) δ 7.76 (d, J = 1.9 Hz, 1H), 7.49 (d,
J = 8.1 Hz, 1H), 7.34 – 7.14 (m, 4H), 6.73 (s, 1H), 6.04 (s, 1H), 0.97 (s, 9H); 13C NMR (101 MHz,
CDCl3) δ 26.7, 42.1, 90.0, 96.2, 111.8, 113.5, 117.4, 119.7, 122.4, 123.1, 124.9, 125.6, 130.5,
131.7, 134.5, 151.3; HRMS (ESI+): calcd for C19H18Br2NO [M+H] 433.9755, found 433.9767.
500g indoline 3 oxidation demonstration:
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To a 2 L jacket flask with an overhead stir were charged indoline 3 (500 g), acetonitrile (1.5 L)
and [Cu(MeCN)4](BF4) (17.2 g) under nitrogen. The reaction mixture was heated to 35 oC and
charged with tert-Butylperoxy 2-ethylhexyl carbonate (TBPC, 367 mL) in 1.5 h via pump. The
reaction was aged at 35 oC until completion (2.1 h). The resulting slurry was then cooled down
to rt, filtered. The cake was then washed with 1 L MeCN once, 2 L MeCN/water (1:1, v/v) once,
and 2 L water once. The cake was then dried under vacuum with N2 sweep for 24 h. total 467 g
indole 4 was obtained with 98.8 NMR wt%, 99.9% LCAP, and 99.9% ee. 92% isolated yield. Assay
about 3% mother liquor loss.
Experimental Procedure for Spin Trap of Proposed tert-Butoxy Radical for X-band cw-EPR
Observation: DMPO (5,5-Dimethyl-1-pyrroline N-oxide) was used as the spin trap molecule. The
EPR sample solution was made by mixing Solution A (60mM [Cu(MeCN)4](BF4) in MeCN) and
Solution B (60mM TBPC and 60mM DMPO in MeCN) at 1:1 v/v ratio, and 40 uL of the resulting
mixture was quickly transferred to a glass capillary tube for reaction monitoring by EPR
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spectroscopy. A broad quartet signal between 3000-3300G arises from Cu2+ (spin 3/2)
produced during the reaction, which plateaus after 3hours signalling reaction completion. The
DMPO adduct produces a sharp multiplet at 3330-3390G, which quickly builds up and then
decays within an hour. The relatively short signal duration reflects limited stability of the DMPO
adduct. Spectral simulation yielded hyperfine coupling constants aN, aHβand aHγ of 13.3G,
7.7G, and 0.9G respectively. At 4 hours, an aliquot of the original mixture was sampled, diluted
100x in MeCN, and analyzed by direct infusion MS. MS (ESI+): calcd for C10H20NO2 [M+H] 187,
found 187.3.35
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Acknowledgements
We thank Renee K. Dermenjian, Justin R. Denton, Aldo Rancier, Peter G. Dormer, Jinchu Liu, Lisa
Frey, Wilfredo Pinto, Joseph Gouker, and Heather Wang for analytical and separations support.
We thank Dan DiRocco, Guy Humphrey, Peter Maligres, Kevin Maloney, Louis-Charles Campeau,
Kevin Campos for helpful discussions.
Supporting Information: Summary of high-throughput experimentation results, EPR study
results, chiral HPLC for ee assessment, and copies of 1H and 13 C NMR spectra.
References:
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(a) Tilstam, U.; Harre, M.; Heckrodt, T.; Weinmann, H. Tetrahedron Lett. 2001, 42, 5385-
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(a) Clark, J.; Macquarrie, D. Handbook of Green Chemistry & Technology Blackwell
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5
The other component of Zepatier is Grazoprevir.
(a) Mangion, I. K.; Chen, C.; Li, H.; Maligres, P.; Chen, Y.; Christensen, M.; Cohen, R.; Jeon,
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2310-2313. During the preparation of this manuscript, an elegant syntheis of Elbasvir was
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Tudge, M. T.; Campeau, L-C.; Campos, K. R. J. Am. Chem. Soc. 2015, 137, 13728-13731.
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For a photo-redox Elbasvir indoline oxidation using an Ir catalyst, see: Yayla, H. G.; Peng,
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Li, H.; Chen, C.; Nguyen, H.; Cohen, R.; Maligres, P.; Yasuda, N.; Mangion, I.; Zavialov, I.;
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Reibarkh, M.; Chung, J. Y. L. J. Org. Chem. 2014, 79, 8533-8540.
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Buitrago Santanilla, A.; Regalado, E. L.; Pereira, T.; Shevlin, M.; Bateman, K.; Campeau, L-
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C.; Schneeweis, J.; Berritt, S.; Shi, Z.; Nantermet, P.; Liu, Y.; Helmy, R.; Welch, C. J.; Vachal, P.;
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For details, see S.I.
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Regulation specification of indole 4 is set at 99.2% ee and experiments shown that the
ee upgrade of indole 4 with low ee by recrystallization was not practical. The new reaction
conditions need to provide the indole 4 in more than 99.2% ee.
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For the use of TBHP in tertiary amine oxidation, see: (a) Murahashi, S-I.; Naota, T.;
Yonemura, K. J. Am. Chem. Soc. 1988, 110, 8256-8258. (b) Li, Z.; Li, C-J. J. Am. Chem. Soc. 2004,
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4628-4633. (b) Boess, E.; Schmitz, C.; Klussmann, M. J. Am. Chem. Soc. 2012, 134, 5317-5325.
For a proposed catalytic cycle please see the SI section.
13
Bach, R. D.; Ayala, P. Y.; Schlegel, H. B. J. Am. Chem. Soc. 1996, 118, 12758-12765.
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One proposal for the formation of the of the side product 5 is the combination of tert-
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butylperoxy radical with radical 10 and a following benzylic oxidation of the CH2 to ketone.
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For recent elegant advances in this field, see: (a) Wendlandt, A. E.; Stahl, S. S. J. Am.
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