Intramolecular C(sp3)-N coupling by oxidation of benzylic C,N-dianions

Article abstract of DOI:10.1002/anie.201209591

What a couple! An intramolecular, C(sp³)-N coupling to afford azacycles is reported. This reaction proceeds through the oxidation of benzylic C,N-dianions with iodine and builds on an earlier discovery during the synthesis of the natural produc

Full text of DOI:10.1002/anie.201209591

Angewandte
Chemie
DOI: 10.1002/anie.201209591
Heterocycle Synthesis
3
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Intramolecular C(sp ) N Coupling by Oxidation of Benzylic C,N-
Dianions**
Jenna L. Jeffrey, Emily S. Bartlett, and Richmond Sarpong*
The ability to effect direct, carbon–nitrogen bond formation
3
ꢀ
ꢀ
between an N H group and a C(sp ) H group by the formal
loss of H2 would significantly enhance the existing toolbox of
synthetic methods to build complex nitrogen-containing
molecules. Such a transformation, particularly involving
N,N-dialkyl secondary amines, would complement processes
such as reductive amination and would obviate the require-
ment of a preoxidized coupling partner (e.g., a carbonyl
group). Although the Hofmann–Lçffler–Freytag (HLF) reac-
tion[1] and its associated modern variants[2] offer one such
alternative, preoxidation of the nitrogen partner is usually
required and success remains limited to the formation of
specific ring sizes. For example, although five-membered rings
are readily formed using the HLF reaction, six- and seven-
membered rings are more difficult to obtain. Thus, a general,
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one-pot, C(sp ) N coupling reaction would be highly desir-
able.[3–5]
ꢀ
Despite notable recent advances in oxidative C C bond
3
formation between two C(sp ) H groups,[6,7] the correspond-
ꢀ
3
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ing C(sp ) N coupling remains underdeveloped. In 2008,
during the total synthesis of the Lycopodium alkaloid
lyconadin A (3; Scheme 1),[8] we demonstrated the efficient,
one-pot, conversion of amine 1 into caged pentacycle 2.
Subsequently, we showed that the oxidation of the C,N-
dianion with iodine likely occurs by a single-electron trans-
3
fer.[8b] This net oxidative C(sp ) N coupling represented
ꢀ
a first step toward the more ambitious goal of a general
C(sp ) N coupling. The cyclization of amine 1 to caged
pentacycle 2 required the deprotonation of a moderately
acidic, pseudo benzylic methylene group (see 1; pKa = ca. 34
in THF)[9] in a rigid, caged system.
3
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Scheme 1. One-pot C(sp ) N bond formation.
unbiased substrates could participate in this reaction, 2) sig-
ꢀ
As such, several challenges for this one-pot coupling
method remained, including whether 1) conformationally
nificantly less-acidic C H bonds (e.g., a benzylic methyl
group; pKa of ca. 41)[10,11] could be employed, and 3) if less-
nucleophilic Li amides, for example Li N-acyl amides, could
serve competently in the reaction. Herein, we report the
[*] J. L. Jeffrey, E. S. Bartlett, Prof. R. Sarpong
Department of Chemistry, University of California, Berkeley
Berkeley, CA 94720 (USA)
successful realization of these goals.
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To begin addressing the challenge of the direct C(sp ) N
coupling between benzylic carbon groups and amines, we
selected tolylamine 4 (Table 1) for our studies.[12] In contrast
to 1, tolylamine 4 lacks any conformational bias that could
E-mail: rsarpong@berkeley.edu
[**] We thank Dr. Vishnumaya Bisai (IISER Bhopal), Dr. Andrꢀ Isaacs
(College of the Holy Cross (USA)), and Erica D’Amato (visiting
undergraduate Amgen Scholar, 2011) for assistance with the
preparation of starting materials for an initial study. This work was
supported by the NIH-USA (NIGMS RO1 GM86374) and
a Research Scholar Grant from the American Cancer Society-USA
(RSG-09-017-01-CDD to R.S.). R.S. is a Camille Dreyfus Teacher
Scholar. J.L.J. is grateful to the NSF for a graduate fellowship. E.S.B
was supported by a Chemical Biology Interface Training Grant from
the NIH (T32 GM066698). We are grateful to Eli Lilly, Abbott, and
Roche for unrestricted financial support.
enforce a complex-induced proximity effect[13] on the C N
ꢀ
bond formation subsequent to the generation of the C,N-
dianion. Not surprisingly, under the reaction conditions that
led to the successful conversion of 1 into 2, the starting
material (4) was recovered unchanged. Starting material was
also recovered from the reaction carried out at an increased
reaction temperature of 08C (Table 1, entry 1). We hypothe-
sized that a Lewis acid additive could act as a template to
control the conformation of the dianion generated from 4 (by
analogy to the probable proximity effect for the dianion
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201209591.
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[a]
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Table 1: Optimization studies of the C N bond formation.
Entry
Additive
Result[b]
1
2
3
4
5
6
none
4 recovered
4 recovered
SnCl2
CuCl2
CuCl
B(OMe)3
ZnCl2
5 (trace) + 4 (major)
5 (trace) + 4 (major)
5 (9%) + 4 (16%) + unidentified by-products
5 (54%) + 4 (8%)
[a] Reaction conditions: nBuLi (2.2 equiv), THF, 0 8C, 2 h, then additive
(1.1 equiv) 1 h, then I2 (1.3 equiv), 0 8C!23 8C, 2 h. All reactions were
conducted at a concentration of 0.3m of 4 in THF. [b] Yield determined
by 1H NMR analysis using hexamethylenetetramine (HMTA) as an
internal standard. THF=tetrahydrofuran.
Scheme 2. The prepared isoindolines. Reaction conditions: Substrate
in THF (0.075m), nBuLi (2.2 equiv), 08C, 2 h, then ZnCl2 (1.1 equiv),
1 h, then, I2 (1.3 equiv); warm to 238C over 2 h. Because of the
inherent instability of the isoindoline products, the yields were
determined by H NMR analysis using HMTA as an internal standard.
[a] The amine precursor to isoindoline 8 was found to be volatile,
which may account for the reduced yield of 8. THF=tetrahydrofuran.
generated from 1)[14] and furthermore, could facilitate depro-
tonation of the benzylic methyl group by breaking down
organolithium aggregates.[15] To that end, we investigated
several additives. Stannous chloride, cupric chloride, and
cuprous chloride were ineffective and led mostly to the
recovery of the starting material (entries 2–4). However,
trimethyl borate (see entry 5), which we investigated as an
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additive on the basis of the successful oxidative C N bond-
forming reaction reported by Shenvi and co-workers,[16] led
mostly to decomposition but gave an encouraging 9% yield of
the product, along with the starting amine 4 (16% recovery).
Pleasingly, ZnCl2 proved to be effective as an additive and led
to the formation of isoindoline 5 in 54% yield (as determined
by 1H NMR analysis)[17] along with some recovered 4 (8%). A
slight improvement in the yield of 5 (59% yield; 68% yield
based on remaining starting material) could be obtained by
conducting the reaction at a lower concentration of 0.075m in
THF. Although the balance of the material was mostly
accounted for by nonspecific decomposition, trace amounts of
imine and iodinated by-products were formed as well.
Generally, the yield of isolated 5 was low because of the
instability of the isoindoline moiety.
groups relative to methyl groups by using alkyllithium
bases.[18–20] N-Aryl substrates yield only small amounts of
the corresponding isoindolines (see 16), thus indicating
a deleterious effect of N-aryl substitution on the reaction.
Overall, the formation of isoindolines by the C,N-dianion
oxidation protocol proceeds in modest to good yield, which is
partly attributable to the stated inherent instability of
3
alkylated isoindolines.[21] To our knowledge, these C(sp ) N
ꢀ
couplings cannot be effected using any other established
methods.
3
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The one-pot oxidative C(sp ) N coupling illustrated in
Scheme 2 spurred an investigation of the dianion formation/
oxidation in a more challenging system involving amide
substrates that would generate less nucleophilic lithium
amides.[22] With our established reaction conditions, N-
acylated isoindolines 17 and 18 (Scheme 3) were formed in
good yields. Unlike the alkylated isoindoline compounds
(Scheme 2), these acylated variants could be purified without
substantial loss of material. Furthermore, isoindolinones (19–
23a) were also formed in modest to good yield. Notably,
products such as 21 were formed without competing ortho
lithiation of the dimethoxybenzene moiety and a methylene
As illustrated in Scheme 2 (only products are shown), the
optimal conditions identified in Table 1, entry 6, with ZnCl2 as
the additive, are applicable to a range of tolyl substrates and
give the corresponding isoindoline products. In the case of 6,
a tertiary amine group, which could lead to competing
lithiation elsewhere, is tolerated. In addition, lithiation of
the pendant phenyl group present in 7 does not appear to
significantly compete with the desired reaction. Steric bulk
proximal to the secondary amine group does not adversely
affect the efficiency of the reaction (compare yields of 5–7 and
8–11). Additionally, substituents on the benzenoid portion of
the substrates are tolerated, including an alkyl group (see 12),
which could undergo lateral deprotonation, and a methoxy
group (see 13), which could promote ortho lithiation. Under
ꢀ
C H bond could be functionalized with good fidelity (see
isoindolinone 23b).
Using our protocol, even substrates that form six- and
seven-membered rings (Scheme 4), the formation of which is
not possible using the HLF or Suꢀrez reactions, participate in
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the oxidative C(sp ) N coupling. For example, N,N-dialkyl
the current conditions,
amine 24a yields seven-membered azacycle 25a in 51% yield
under our standard reaction conditions, whereas amide 24b
affords 25b in 46% yield (as determined by NMR spectros-
copy).[23] Notably, an attempted HLF reaction with the N-
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C(sp ) N coupling involving a methylene group proceeds in
reduced yield (see 15). This result likely points to the
associated kinetic challenge in deprotonating methylene
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synthetic and medicinal chemistry communities. They are
constrained analogues of the established pharmacophore 2-
(3-pyridyl)ethylamine,[25] which has led to their investigation
in combating, for example, Alzheimerꢁs disease.[26] As shown
in Scheme 4C, under our standard reaction conditions,
pyridoazepine 29 is formed in 74% yield from the conforma-
tionally flexible substrate 28. Additionally, methoxypicoline
derivative 30 yields benzo[f][1,7]naphthyridine 31 subsequent
3
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to sequential oxidative C(sp ) N coupling and manga-
nese(IV) oxide oxidation.[27] This overall transformation
presents a novel entry to naphthyridines, which also have
interesting documented biological properties.[28]
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Finally, in addition to C(sp ) N coupling of C,N-dianions
under oxidative conditions, we have observed an interesting
ꢀ
C C bond-forming reaction where the course of the reaction
can be diverted to a different outcome (Scheme 5). Thus,
Scheme 3. The prepared N-acyl isoindolines and isoindolinones. All
yields shown are of the isolated products unless otherwise stated.
Reaction conditions: Substrate in THF (0.075m), nBuLi (2.2 equiv),
08C, 2 h, then ZnCl2 (1.1 equiv), 1 h, then, I2 (1.3 equiv); warm to
238C over 2 h. [a] Yield of 23b was determined by 1H NMR analysis
using HMTA as an internal standard. THF=tetrahydrofuran.
ꢀ
Scheme 5. A divergent C C bond-forming reaction of C,N-dianions.
treating pivalamide 32 with 2.2 equivalents of nBuLi presum-
ably yields N,O-dilithio intermediate 33. A standard acidic
workup affords imine 34 (following dehydration) in 86%
yield. Alternatively, oxidative workup by the addition of
1 equivalent of molecular iodine yields amide 36 in 55%
yield.[29] Amide 36 likely forms via N-iodo intermediate 35 (or
the corresponding O-iodo compound), which undergoes a loss
ꢀ
of isobutylene and LiI. These unusual C C bond-forming
reactions offer new opportunities for the synthesis of nitrogen
heterocycles and will form the basis for future studies in our
laboratory.
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In conclusion, we report a one-pot, C(sp ) N coupling
between the anions of benzylic carbon groups (pKa of ca. 41)
and nitrogen-based anions to yield various azacycles, includ-
ꢀ
Scheme 4. Oxidative C N bond formation to form six- and seven-
ing isoindolines and isoindolinones. Our optimal reaction
membered rings. Reaction conditions: a) nBuLi (2.2 equiv), THF, 0 8C,
2 h; then ZnCl2 (1.1 equiv), 1 h; then I2 (1 equiv), 0 8C!23 8C, 2 h.
b) MnO2 (excess), CH2Cl2, 23 8C, 12 h [a] Yield of 25b determined by
1H NMR analysis using HMTA as an internal standard.
3
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conditions for C(sp ) N coupling are readily applied to:
1) tolyl substrates, which are significantly less acidic than our
one prior example with a picoline substrate (i.e., 1), 2) con-
formationally unbiased substrates to effectively form six- and
seven-membered azacycles, and 3) amide substrates that give
rise to less-reactive nitrogen nucleophiles. The scope of the
transformations that we can now achieve sets the stage for
myriad applications, including complex molecule synthesis.
Current efforts are focused on gaining insight into the role of
the ZnCl2 additive in these reactions, as well as expanding the
chloro derivative of 24a or a Suꢀrez reaction with 24b led
only to nonspecific decomposition.[17]
In a significant development, 5,6,7,8-tetrahydro-1,7-naph-
thyridine (THN) derivative 27 is formed in 64% yield from
26.[24] THNs have attracted considerable attention from the
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of 1 in THF, see: J. M. Gruver, S. P. West, D. B. Collum, R.
Sarpong, J. Am. Chem. Soc. 2010, 132, 13212 – 13213.
scope of C(sp ) N bond formation to include substrates that
ꢀ
possess sterically congested C H bonds (e.g., methine
[15] For the influence of additives on alkyllithium basicity, see: For
LiX a) D. Seebach, V. W. Bauer, Helv. Chim. Acta 1984, 67,
1972 – 1988; For amine bases b) T. L. Brown, Pure Appl. Chem.
1970, 23, 447 – 462; c) B. J. Wakefield, The Chemistry of Organo-
lithium Compounds, Pergamon, Oxford, 1974.
groups).
Received: November 30, 2012
Published online: && &&, &&&&
[16] S. V. Pronin, M. G. Tabor, D. J. Janson, R. A. Shenvi, J. Am.
Chem. Soc. 2012, 134, 2012 – 2015.
[17] See the Supporting Information for details.
ꢀ
Keywords: carbanions · C N coupling · dianions ·
nitrogen heterocycles · oxidative coupling
.
[18] The kinetic acidity of toluene is known to be higher than that of
ethylbenzene. For example, methyl substitution (e.g., toluene!
ethylbenzene) has been documented to decrease reactivity with
lithium cyclohexylamide base. For a discussion, see: A. Streit-
wieser, D. E. Van Sickle, J. Am. Chem. Soc. 1962, 84, 249 – 250.
[19] For a pertinent discussion of the relative rates of carbanion
generation from N-methyl versus N-ethyl amides, see: D. R.
Hay, Z. Song, S. G. Smith, P. Beak, J. Am. Chem. Soc. 1988, 110,
8145 – 8153.
[20] The kinetic difficulty in deprotonating methylene positions
relative to a methyl position has been applied successfully in
directed ortho-metalation chemistry, see: V. Snieckus, Chem.
Rev. 1990, 90, 879 – 933.
[21] The synthesis and purification of isoindolines is known to
proceed in low yield, see: a) R. A. Barnes, J. C. Godfrey, J. Org.
Chem. 1957, 22, 1038 – 1043; b) I. Ahmed, G. W. H. Cheeseman,
B. Jacques, R. G. Wallace, Tetrahedron 1977, 33, 2255 – 2258;
c) Y.-X. Wang, S. Mabic, N. Castagnoli, Jr., Bioorg. Med. Chem.
1998, 6, 143 – 149; d) D.-R. Hou, M.-S. Wang, M.-W. Chung, Y.-
D. Hsieh, H.-H. G. Tsai, J. Org. Chem. 2007, 72, 9231 – 9239;
e) T. Ohmura, A. Kijima, M. Suginome, J. Am. Chem. Soc. 2009,
131, 6070 – 6071; f) The mass balance in these reactions was
accounted for by nonspecific decomposition products.
[22] Amides have been demonstrated as competent bases for
deprotonation of related systems, see: a) R. L. Vaulx, W. H.
Puterbaugh, C. R. Hauser, J. Org. Chem. 1964, 29, 3514 – 3517;
b) G. S. Poindexter, J. Org. Chem. 1982, 47, 3787 – 3788.
[23] In the absence of ZnCl2 and iodine, 24b is converted into
phenanthrylamine i in 49% yield.
[1] For a review on the Hofmann–Lçffler–Freytag reaction, see:
a) L. Feray, N. Kuznetsov, P. Renaud in Radicals in Organic
Synthesis, Vol. 2 (Ed.: P. Renaud), Wiley-VCH, Weinheim, 2001,
pp. 254 – 256; b) L. Stella in Radicals in Organic Synthesis Vol. 2
(Ed.: P. Renaud), Wiley-VCH, Weinheim, 2001, pp. 409 – 426.
[2] For example, the Suꢀrez modification, see: C. G. Francisco, A. J.
Herrera, E. Suꢀrez, J. Org. Chem. 2003, 68, 1012 – 1017.
[3] For an elegant recent C(sp ) N forming reaction involving
3
ꢀ
nitrenium-like ions generated from 1-aza-2-azoniallene salts,
see: D. A. Bercovici, M. Brewer, J. Am. Chem. Soc. 2012, 134,
9890 – 9893.
3
ꢀ
[4] Several transition-metal-catalyzed oxidative C(sp ) N bond-
forming reactions have been reported. However, in all these
cases, a primary amine derivative that is attached to an electron-
withdrawing group is required. For selected recent accounts, see:
a) J. Du Bois, Org. Process Res. Dev. 2011, 15, 758 – 762; b) C. G.
Espino, J. Du Bois in Modern Rhodium-Catalyzed Organic
Reactions (Ed.: P. A. Evans), Wiley-VCH, Weinheim, 2005,
pp. 379 – 416.
II
2
ꢀ
[5] For Pd -catalyzed oxidative C(sp ) N bond-forming reactions,
see: a) T.-S. Mei, X. Wang, J.-Q. Yu, J. Am. Chem. Soc. 2009, 131,
II
ꢀ
10806 – 10807; for Pd -catalyzed allylic C H amination, see:
b) S. A. Reed, M. C. White, J. Am. Chem. Soc. 2008, 130, 3316 –
3318. In these cases, amines attached to electron-withdrawing
groups are required.
[6] For a review, see: C. S. Yeung, V. M. Dong, Chem. Rev. 2011, 111,
1215 – 1292.
[7] For recent examples of applications in complex molecule
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[8] a) A. Bisai, S. P. West, R. Sarpong, J. Am. Chem. Soc. 2008, 130,
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Sarpong, J. Am. Chem. Soc. 2009, 131, 11187 – 11194.
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3232 – 3234.
[10] F. G. Bordwell, Acc. Chem. Res. 1988, 21, 456 – 463.
[11] This approximate pKa value is inferred from the reported pKa for
toluene, see: a) A. Streitwieser, M. R. Granger, F. Mares, R. A.
Wolf, J. Am. Chem. Soc. 1973, 95, 4257 – 4261; b) A. Streitwieser,
D. W. Boerth, J. Am. Chem. Soc. 1978, 100, 755 – 759.
[12] We anticipated that 4 would undergo lateral lithiation on the
basis of the studies of Smith et al., who have previously shown
that N’-(2-methylbenzyl)-N,N-dimethylurea and N-(2-methyl-
benzyl) pivalamide undergo lateral lithiation to form the
corresponding dilithiated species. See: K. Smith, G. A. El-Hiti,
A. S. Hegazy, Synthesis 2010, 1371 – 1380.
[24] For a recent approach to THNs, as well as a discussion of other
synthetic approaches, see: A. K. Mailyan, A. S. Peregudov, P. H.
Dixneuf, C. Bruneau, S. N. Osipov, J. Org. Chem. 2012, 77, 8518 –
8526.
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oxidations. See: W.-R. Li, M.-N. Hsu, H.-H. Chou, S. T. Lin, Y.-S.
Lin, Chem. Commun. 2000, 401 – 402.
[28] B. Bachowska, T. Zujewska, ARKIVOC 2001, 77 – 84.
[29] The starting material (i.e., 32, 6%) and 5% of imine 34 was also
obtained.
[13] P. Beak, A. I. Meyers, Acc. Chem. Res. 1986, 19, 356 – 363.
[14] Coordinated solvents removed for clarity. For a discussion of the
aggregation state of the dianion generated upon deprotonation
4
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Angew. Chem. Int. Ed. 2013, 52, 1 – 5
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Chemie
Communications
Heterocycle Synthesis
J. L. Jeffrey, E. S. Bartlett,
R. Sarpong*
&&& — &&&
3
ꢀ
Intramolecular C(sp ) N Coupling by
Oxidation of Benzylic C,N-Dianions
What a couple! An intramolecular, C-
natural product lyconadin A. The current
study employs conformationally unbiased
3
ꢀ
(sp ) N coupling to afford azacycles is
ꢀ
reported. This reaction proceeds through
the oxidation of benzylic C,N-dianions
with iodine and builds on an earlier
discovery during the synthesis of the
substrates with less acidic C H bonds
and less reactive nitrogen nucleophiles.
ZnCl2 was identified as an important
additive.
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