N-Hydroxyphthalimidyl diazoacetate (NHPI-DA): A modular methylene linchpin for the C-H alkylation of indoles

Article abstract of DOI:10.1039/d1cc01026c

Despite the extensive studies on the reactions between conventional diazocompounds and indoles, these are still limited by the independent synthesis of the carbene precursors, the specific catalysts, and the required multi-step manipulation of the products. In this work, we explore redox-Active carbenes in the expedited and divergent synthesis of functionalized indoles. NHPI-DA displays unusual efficiency and selectivity to yield insertion products that can be swiftly elaborated into boron and carbon substituents that are particularly problematic in carbene-mediated reactions.

Full text of DOI:10.1039/d1cc01026c

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N-Hydroxyphthalimidyl diazoacetate (NHPI-DA):
a modular methylene linchpin for the C–H
alkylation of indoles†
Cite this: Chem. Commun., 2021,
57, 4532
Received 12th March 2021,
Accepted 29th March 2021
Rajdip Chowdhury
and Abraham Mendoza
*
DOI: 10.1039/d1cc01026c
rsc.li/chemcomm
Despite the extensive studies on the reactions between conven- displayed a surprisingly enhanced reactivity and selectivity in asym-
tional diazocompounds and indoles, these are still limited by the metric cyclopropanation reactions.6 In this work we explore the
independent synthesis of the carbene precursors, the specific utility of redox-active carbenes in C–H functionalization
catalysts, and the required multi-step manipulation of the products. (Scheme 1B), which is unprecedented as far as we know. The
In this work, we explore redox-active carbenes in the expedited and transformation of indoles 10 into C3-alkyl derivatives 11 is
divergent synthesis of functionalized indoles. NHPI-DA displays particularly attractive for their importance in medicinal chemistry,
unusual efficiency and selectivity to yield insertion products that natural products research, material science and chemical
can be swiftly elaborated into boron and carbon substituents that biology.8–13 The abundant literature on the reaction of metal
are particularly problematic in carbene-mediated reactions.
The systematic assembly of ubiquitous methylene units is currently
limited by the different chemistries and reagents that are required
to introduce various functions in the targeted aliphatic groups. This
is the case for the conversion of heteroarenes (1) into important
C–H alkylated derivatives 2 (R; Scheme 1A).1,2b,3 The highly electro-
philic carbenes4 involved in these reactions are incompatible with
most electron-rich or labile functions. In particular, boryl-,5a aryl-,5b
alkyl-,5c,d and vinyl-5e methylidenes 3–6 would directly lead to
valuable products, but are too unstable to participate in selective
intermolecular C–H insertion. To overcome these limitations, our
group envisaged a unified C–H alkylation strategy based on the
early-stage C–H insertion of a versatile redox-active carbene 7,6 and
subsequent late-stage diversification of the resulting intermediate 8
to obtain the modified heterocycles 2.2,7 This way, the initial C–H
insertion would require only one carbene precursor 7 regardless of
the final functionality desired in the products 2. Moreover, these
moieties would even include those inherently incompatible with
geminal carbene intermediates (i.e. 3–6).
Recently, our group has discovered that N-hydroxyphtalimide
(NHPI) esters can be orthogonal to geminal carbene intermediates.6
In particular, the diazocompound reagent NHPI-DA (7a) has
Department of Organic Chemistry, Arrhenius laboratory, Stockholm University,
106 91 Stockholm, Sweden. E-mail: abraham.mendoza@su.se
† Electronic supplementary information (ESI) available. See DOI: 10.1039/
Scheme 1 Heterocycle editing through C–H alkylation with redox-active
carbenes. RAE, redox-active ester; PhthN, phthalimidyl.
d1cc01026c; NMR raw data can be downloaded from Zenodo. See DOI: 10.5281/
zenodo.4652793
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carbenes with indoles4a,d,9–13 reveals that these reactions can complete C3-selectivity, unlike some previous studies with
produce mixtures of C3-8–11 or C2-insertion,12 and cyclopropana- C2 : C3 insertion selectivity issues.10 Using 13 as catalyst, conven-
tion of the C2,C3–p-bond.9c,11d,13 The mechanism of this reaction tional diazocompounds like ethyl diazoacetate are substantially
has been discussed in several studies.9b,c,10c,11b,d,13c These specific less efficient (62%, see ESI†), and redox-active a-aryldiazoacetate
difficulties add to the more general challenge of taming the reagents6a were unreactive. These observations illustrate the
reactivity of carbenes bearing labile leaving groups directly con- importance of the match between the catalyst and the carbene
nected to the highly reactive carbon.14
precursor for efficient insertion.
The reaction of the redox-active diazoacetate NHPI-DA (7a)
The performance and the selectivity of the insertion were
in the model N-benzylindole (10a) was explored using a collec- explored in a series of indoles functionalized in all positions
tion of the most successful catalysts that were used with (Scheme 2). The substitution at the nitrogen atom is known to
conventional carbene precursors.9–13 It was found that the be crucial at defining the reactivity of the indole core.8–13 In our
redox-active handle had a profound effect in the reactivity of case, various types of aliphatic (12a–j,m–ac), aromatic (12k),
the derived metal–carbene intermediate.6 The desired insertion and silicon (12l) substituents are suitable, including common
product 12a is obtained only in low yields using rhodium, functionality found in natural products (12b), and a cyclopro-
copper and iron catalysts that are successful with conventional pane drugs (12i). A wide range of functionalized aliphatics
diazoacetates (see ESI†). Extensive decomposition of NHPI-DA bearing ketone (12c),16 halide (12d), ester (12f), ether (12g)
(7a) was observed but no other by-products were detected in the and nitrile (12h) functions are tolerated in this carbene transfer
reaction crude by 1H-NMR. In line with our previous studies reaction, allowing for further diversification. Also, the unhin-
with chiral metallacyclic ruthenium catalysts,6b it was found dered olefin in 12j highlights the chemoselective insertion in
that the achiral analogue 13 (Scheme 2)15 displayed optimal the indole nucleus over the competing cyclopropanation that
efficiency and selectivity. To the best of our knowledge, ruthe- we have previously reported under similar conditions.6b This
nium metallacycles have not been reported to catalyze carbene may be due to the higher nucleophilicity of the indole com-
transfer reactions on indoles. We found that the slow addition pared to the olefin, and the particular affinity of the metal–
of the diazocompound 7a is optional, and similar results are carbene intermediate for the former. Expectedly, indoles that
obtained adding as little as 1.25 equiv. 7a in one shot (see ESI†). are unfunctionalized at nitrogen (i.e. 1H-indole) are unsuitable
The performance of NHPI-DA (7a) contrasts with conventional due to competing N–H insertion, but conventional protecting
diazocompounds that often require larger excess of the groups like benzyl (12a), allyl (12j) and trialkylsilyl (12l) can
reagents and slow addition in similar reactions with provide access to the corresponding NH-indole derivatives, if
indoles.8c,9a,b,11a,c,13a,d Moreover, the product is obtained with desired. It was found that electron-withdrawing protecting
Scheme 2 Scope of the C3-selective insertion of NHPI-DA (7a) into functionalized indoles. Conditions: 10 (0.2–0.3 mmol), 7a (1.25 equiv.), CH2Cl2
(0.1 M), 0.25–14 h, r.t. Isolated yields. a Slow addition (0.25–14 h; see ESI†). b 7a (0.3 mmol), 10 (2.0 equiv.), [Ru(p-cymene)Cl2]2 (2 mol%).
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groups at nitrogen deactivate the indole towards functionaliza-
tion by electrophilic carbene intermediates. In the neighboring
C2 position different aromatics (12m–p) are tolerated, includ-
ing fluorinated groups (12o) and extended aromatics (12p).
Aliphatic substituents are also tolerated (12q,r), despite the
lower efficiency observed when a sterically hindered substitu-
ent is placed in the neighboring carbon (12r). The benzo-fused
ring in the indole framework can also carry a wide range of
functionality in C4 (12s), C5 (12t–y), C6 (12z) and C7 (12aa,ab),
which include halides (12s–u), boronic ester (12w), aldehyde
(12ab), and even an electron-rich heterocycle (12y). It is impor-
tant to highlight that slow addition has been found to be
optional in most cases (see Scheme 2 for details), and the
products 12 can often be obtained in good yields adding NHPI-
DA (7a) at once without a syringe pump. Despite the structural
diversity of indoles 10a–ab used in this study, we have observed
complete regioselectivity for the C3 insertion in all cases. This
feature motivated further exploration of the insertion reaction
at the C2 position of the indole nucleus with C3-functionalized
substrates.10a,b,12 Given the complete C3 selectivity observed in
C2-unfunctionalized substrates with the metallacyclic catalyst
13, its unsuitability for this purpose came as no surprise.
After extensive experimentation, it was found that the simpler
[Ru(p-cymene)Cl2]2 that had an intermediate performance
with N-alkyl indoles (see ESI†), was an effective catalyst on
Scheme 3 One-pot C3 methylborylation of functionalized indoles. Con-
ditions: 10 (0.2–0.3 mmol), 7a (1.25 equiv.), CH2Cl2 (0.1 M), 0.25–14 h, r.t.,
then NiCl2ꢀ6H2O (0.10 equiv.), 4,40-di-t-Bubipy (0.13 equiv.), MgBr2ꢀOEt2
(1.5 equiv.), B2pin2 (3.0 equiv.), MeLi (3.3 equiv.), 0 1C to r.t., 2 h, Ar. Yields
were determined by 1H-NMR using 1,1,2,2-tetrachloroethane as internal
standard. Isolated yields in parenthesis. Pin, pinacol.
NH-indole substrates to produce the derivatives 12ac,ad in functions. To put these results in perspective, boronic ester 11b
good yields. The use of [Ru(p-cymene)Cl2]2 in the insertion of has been synthesized through two different routes that require
NH-indoles has been reported using a-aryldiazoacetates, which three steps from N-methylindole,2b,3 and can be now accom-
are significantly more stabilized than NHPI-DA (7a).12b Indeed, plished in a one-pot operation using the same material. The
the selective C2-insertion into C3-substituted indoles with methylborylated indoles 11 have variable stability during chro-
simple diazoacetates is rare9c,10c compared to stabilized matographic purification, which accounts for the lower isolated
carbene precursors bearing additional aryl or electron- yields obtained in some cases.
withdrawing substituents.10a,b,17 Overall, the breadth of the
The functionalized indole intermediates 12a,l are also well-
scope, selectivity and efficiency demonstrated by NHPI-DA suited for mild C–C coupling with different types of organome-
(7a) are remarkable in the context of related carbene transfer tallics and Michael acceptors (Scheme 4).7 The corresponding
reactions to indoles,9c,10,11d and further demonstrates the unu- products 11n–ab cannot be obtained through alternative carbene
sual reactivity and selectivity of redox-active carbenes.6
transfer reactions due to the particular instability of intermediates
With satisfactory conditions for the redox-active carbene 4–6 (Scheme 1).5b–e After decarboxylative arylation (Scheme 4) the
transfer reaction, we studied the transformation of products products 11n–p were obtained without the need to prepare and
12 into methylborylated indoles 11a–m to illustrate the edge of optimize the catalytic system for several aryl-diazomethane pre-
this strategy at delivering the formal products of unavailable cursors. Vinyl carbenes are prone to oligomerize and isomerize
borylmethylidene5a (3) C–H insertion (Scheme 3). Among but these substituents can be seamlessly incorporated to deliver
the various decarboxylative borylation protocols developed in the skipped unsaturated products 11q–s. In contrast with classic
recent years,2 we found that the conditions initially developed SN20 allylations of indoles,18 the products 11q–s are obtained with
by Baran were most effective in this context.2a Moreover, we high regioselectivity. Only minimal isomerization of the pendant
could telescope the borylation reaction performing a solvent alkene was observed in 11s. Functionalized alkyl groups (11t–ab),
switch, thus obtaining products 11a–m in a one-pot reaction including protected alcohol (11t), heterocycle (11u), halide (11v),
from the functionalized indoles 10. Using this protocol, we olefin (11w), or cyclopropane (11x) groups can also be included.7d
could obtain methylborylated indoles with decorated aliphatics Michael acceptors can also be utilized as alkyl group precursors in
(11a–f), aromatic (11g) or silylated (11h) functions at nitrogen. Giese-type reactions7b to deliver ketone (11z), nitrile (11aa), or
Functionalization at other positions in the indole nucleus ester (11ab) functions. Unlike conventional alkylation reactions
(11i–m) does not affect the performance of the borylation that require the synthesis of the corresponding alkyl halides and
reaction. Due to the functional group tolerance of both the high temperatures,1 these reactions occur at room temperature
C–H insertion, and the decarboxylative borylation reactions the using a unified retrosynthetic approach. The strategic value of the
methylborylated indoles can be uneventfully decorated with linchpin approach presented herein is further illustrated by the
ester (11c), nitrile (11d), ether (11e), silicon (11h) or halide (11k) product 11aa, which required 6 synthetic steps to be prepared
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Angew. Chem., Int. Ed., 2017, 56, 16602; (d) P. Rulliere, G. Benoit,
E. M. D. Allouche and A. B. Charette, Angew. Chem., Int. Ed., 2018,
57, 5777; (e) B. Herle, P. M. Holstein and A. M. Echavarren,
ACS Catal., 2017, 7, 3668.
6 (a) Z. Yu and A. Mendoza, ACS Catal., 2019, 9, 7870;
´
(b) M. Montesinos-Magraner, M. Costantini, R. Ramırez-Contreras,
M. E. Muratore, M. J. Johansson and A. Mendoza, Angew. Chem., Int.
Ed., 2019, 58, 5930.
7 For selected decarboxylative C–C coupling reactions, see: (a) J. Cornella,
J. T. Edwards, T. Qin, S. Kawamura, J. Wang, C. M. Pan, R. Gianatassio,
M. Schmidt, M. D. Eastgate and P. S. Baran, J. Am. Chem. Soc., 2016,
138, 2174; (b) T. Qin, L. R. Malins, J. T. Edwards, R. R. Merchant,
A. J. Novak, J. Z. Zhong, R. B. Mills, M. Yan, C. Yuan, M. D. Eastgate and
P. S. Baran, Angew. Chem., Int. Ed., 2017, 56, 260; (c) R. Chowdhury, Z. Yu,
M. L. Tong, S. V. Kohlhepp, X. Yin and A. Mendoza, J. Am. Chem. Soc.,
2020, 142, 20143; (d) T. Qin, J. Cornella, C. Li, L. R. Malins, J. T. Edwards,
S. Kawamura, B. D. Maxwell, M. D. Eastgate and P. S. Baran, Science,
2016, 352, 801.
8 For selected seminal studies, see: (a) G. M. Badger, B. J. Christie,
H. J. Rodda and J. M. Pryke, J. Chem. Soc., 1958, 1958, 1179;
(b) J. R. Piper and F. J. Stevens, J. Heterocycl. Chem., 1966, 3, 95;
(c) W. J. Welstead, H. F. Stauffer and L. F. Sancilio, J. Med. Chem.,
1974, 17, 544; (d) H. Keller, E. Langer and H. Lehner, Monatsh.
Chem., 1977, 108, 123; (e) A. J. Leitch, Y. Bhonoah and C. G. Frost,
ACS Catal., 2017, 7, 5618.
9 For selected C3-insertions with simple diazocompounds, see:
(a) K. J. Hock, A. Knorrscheidt, R. Hommelsheim, J. Ho,
M. J. Weissenborn and R. M. Koenigs, Angew. Chem., Int. Ed.,
2019, 58, 3630; (b) D. A. Vargas, A. Tinoco, V. Tyagi and R. Fasan,
Angew. Chem., Int. Ed., 2018, 57, 9911; (c) M. Delgado-Rebollo,
Scheme 4 Unified alkylation of indoles at room temperature. See ESI† for
details. Isolated yields. a 420 : 1 r.r. b 46 : 1 r.r. c Giese reaction with a
Michael acceptor. r.r., regioisomeric ratio.
from indole,19 and now can be obtained in half of those
operations.
´
A. Prieto and P. J. Perez, ChemCatChem, 2014, 6, 2047.
10 The insertion of diazocompounds sometimes lead to mixtures of
C2- and C3-insertion products. For examples using stabilized dia-
zomalonates, see: (a) M. B. Johansen and M. A. Kerr, Org. Lett., 2010,
12, 4956; (b) R. Gibe and M. A. Kerr, J. Org. Chem., 2002, 67, 6247. For
a related radical coupling method, see: (c) L. W. Ciszewski, J. Durka
and D. Gryko, Org. Lett., 2019, 21, 7028.
11 For selected C3-insertions of a-functionalized diazoacetates, see:
(a) D. T. Boruta, O. Dmitrenko, G. P. A. Yap and J. M. Fox, Chem. Sci.,
2012, 3, 1589; (b) Y. Cai, S.-F. Zhu, G.-P. Wang and Q.-L. Zhou,
Adv. Synth. Catal., 2011, 353, 2939; (c) A. DeAngelis, V. W. Shurtleff,
O. Dmitrenko and J. M. Fox, J. Am. Chem. Soc., 2011, 133,
1650; (d) X.-J. Zhang, S.-P. Liu and M. Yan, Chin. J. Chem., 2008,
26, 716; (e) A. Dasgupta, R. Babaahmadi, B. Slater, B. F. Yates,
A. Ariafard and R. L. Melen, Chemistry, 2020, 6, 2364; ( f ) Z. Yang,
M. Moller and R. M. Koenigs, Angew. Chem., Int. Ed., 2020, 59, 5572;
(g) S. Jana, F. Li, C. Empel, D. Verspeek, P. Aseeva and
R. M. Koenigs, Chem. – Eur. J., 2020, 26, 2586.
In summary, a divergent C–H alkylation of indoles at room
temperature is enabled by a redox-active single carbon linchpin.
The exclusive regioselectivity and high efficiency of the insertion
reaction with a redox-active carbene enable mild editing of the
indole core. These results demonstrate the capacity of redox-active
carbenes to enable formal C–H functionalization reactions in
indoles by carbene intermediates that are problematic or inherently
unstable like boryl-, aryl-, vinyl-, and alkyl-methylidenes.
Conflicts of interest
There are no conflicts to declare.
12 Only stabilized a-aryldiazoacetates and diazomalonates undergo
C2-selective
insertion
on
C3-unfunctionalized
indoles:
Notes and references
1 For representative alternative indole C3-alkylation methods, see:
(a) M. De Rosa and A. Soriente, Eur. J. Org. Chem., 2010, 1029;
(b) H. E. Johnson and D. G. Crosby, J. Org. Chem., 1963, 28, 1246;
(c) A. E. Putra, K. Takigawa, H. Tanaka, Y. Ito, Y. Oe and T. Ohta, Eur.
(a) J. Ghorai, M. Chaitanya and P. Anbarasan, Org. Biomol. Chem.,
2018, 16, 7346; (b) W.-W. Chan, S.-H. Yeung, Z. Zhou, A. S. C. Chan
and W.-Y. Yu, Org. Lett., 2010, 12, 604; (c) S. Dhole, W. J. Chiu and
C. M. Sun,
Adv. Synth. Catal., 2019, 361, 2916.
J. Org. Chem., 2013, 6344; (d) V. Soni, S. M. Khake and B. Punji, ACS 13 For indole cyclopropanation, see: (a) G. Ozuduru, T. Schubach and
Catal., 2017, 7, 4202.
M. M. Boysen, Org. Lett., 2012, 14, 4990; (b) S. J. Hedley,
D. L. Ventura, P. M. Dominiak, C. L. Nygren and H. M. L. Davies,
J. Org. Chem., 2006, 71, 5349; (c) I. D. Jurberg and H. M. L. Davies,
Chem. Sci., 2018, 9, 5112; (d) F. Gnad, M. Poleschak and O. Reiser,
Tetrahedron Lett., 2004, 45, 4277.
2 For selected decarboxylative borylations, see: (a) C. Li, J. Wang,
L. M. Barton, S. Yu, M. Tian, D. S. Peters, M. Kumar, A. W. Yu,
K. A. Johnson, A. K. Chatterjee, M. Yan and P. S. Baran, Science,
2017, 356, eaam7355; (b) A. Fawcett, J. Pradeilles, Y. Wang,
T. Mutsuga, E. L. Myers and V. K. Aggarwal, Science, 2017, 357, 283. 14 (a) C. Schnaars, M. Hennum and T. Bonge-Hansen, J. Org. Chem.,
3 H. Zhang, S. Hagihara and K. Itami, Chem. – Eur. J., 2015, 21, 16796.
4 For selected reviews on a-diazo carbonyl compounds, see:
2013, 78, 7488; (b) Z. Wang, A. G. Herraiz, A. M. del Hoyo and
M. G. Suero, Nature, 2018, 554, 86.
(a) H. M. Davies and S. J. Hedley, Chem. Soc. Rev., 2007, 36, 1109; 15 S. Chanthamath, S. Thongjareun, K. Shibatomi and S. Iwasa, Tetra-
(b) M. P. Doyle, R. Duffy, M. Ratnikov and L. Zhou, Chem. Rev., 2010,
hedron Lett., 2012, 53, 4862.
110, 704; (c) M. P. Doyle, M. Ratnikov and Y. Liu, Org. Biomol. Chem., 16 For our recent ketone synthesis, see: K. Colas, A. C. V. D. dos Santos
2011, 9, 4007; (d) A. Ford, H. Miel, A. Ring, C. N. Slattery,
and A. Mendoza, Org. Lett., 2019, 21, 7908.
A. R. Maguire and M. A. McKervey, Chem. Rev., 2015, 115, 9981; 17 J. M. Antos, J. M. McFarland, A. T. Lavarone and M. B. Francis, J. Am.
(e) Y. Xia, D. Qiu and J. Wang, Chem. Rev., 2017, 117, 13810. Chem. Soc., 2009, 131, 6301.
5 (a) G. Benoit and A. B. Charette, J. Am. Chem. Soc., 2017, 139, 1364; 18 M. Westermaier and H. Mayr, Org. Lett., 2006, 8, 4791.
˜
´
(b) J. Barluenga, N. Quinones, M. Tomas-Gamasa and M.-P. Cabal, 19 (a) M. S. Pedras, Z. Minic, P. D. Thongbam, V. Bhaskar and
Eur. J. Org. Chem., 2012, 2312; (c) A. Greb, J. S. Poh, S. Greed,
C. Battilocchio, P. Pasau, D. C. Blakemore and S. V. Ley,
S. Montaut, Phytochemistry, 2010, 71, 1952; (b) W. Ren, J. Chu,
F. Sun and Y. Shi, Org. Lett., 2019, 21, 5967.
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