Diazo- And transition-metal-free C-H insertion: A direct synthesis of β-lactams

Article abstract of DOI:10.1002/chem.201404990

Carbene intermediates are very useful species for a range of reactions including C-H insertions and cycloadditions. They are most commonly generated by metal-catalyzed release of nitrogen gas from diazo precursors. Herein, we present a novel C-H insertion

Full text of DOI:10.1002/chem.201404990

DOI: 10.1002/chem.201404990
Communication
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Organic Chemistry |Hot Paper|
Diazo- and Transition-Metal-Free CÀH Insertion: A Direct
Synthesis of b-Lactams
Luis F. R. Gomes,[a] Luꢀs F. Veiros,[b] Nuno Maulide,*[c] and Carlos A. M. Afonso*[a]
Efforts to circumvent these hazards include the use of latent
Abstract: Carbene intermediates are very useful species
for a range of reactions including CÀH insertions and cy-
cloadditions. They are most commonly generated by
metal-catalyzed release of nitrogen gas from diazo precur-
sors. Herein, we present a novel CÀH insertion of simple
b-ketoamide substrates, through reaction with (diacet-
oxyiodo)benzene (DIB) in the presence of a base. This un-
precedented transformation bypasses the use of either
diazo precursors or metal catalysts and directly delivers b-
lactam products by an iodonium ylide, in a single step
under mild conditions. Mechanistic studies support the in-
termediacy of a free singlet carbene of unique reactivity
and selectivity.
diazo compounds,[10b,13] sulfur,[14] or iodonium ylides[15] and,
more recently, cyclopropenes[16] among others.[17] Nevertheless,
examples of CÀH insertion employing these surrogates remain
limited,[18] including for alkylidenecarbenes derived from
a-elimination of the corresponding iodonium tetrafluorobor-
ates.[18d]
In line with our prior efforts on intramolecular CÀH insertion
and functionalization reactions,[19] we became interested in
methods that circumvent the use of the diazo moiety for CÀH
insertion. Upon focusing on iodonium ylides we unexpectedly
discovered a direct and unprecedented one-step synthesis of
b-lactams by a formal dehydrogenative coupling[20] of simple
ketoamides that neither requires a metal catalyst nor a diazo
precursor[21,22] and which proceeds under very mild conditions
(below or at room temperature; Scheme 1).
Diazo compounds are often used as carbene precur-
sors due to the ease of nitrogen gas release.[1] This
reaction is usually induced by transition-metal cata-
lysts (e.g. Rh, Cu, Ru, Pd),[2] but photochemical[3] and
thermal[4] decompositions are also known. The result-
ing carbenes[5] undergo many synthetically useful re-
actions such as cyclopropanation,[6] CÀH insertion[7]
and ylide formation.[8,9] The CÀH insertion/CÀC bond
formation reactivity mode is particularly attractive as
it effectively amounts to the activation of an other-
wise unreactive, remote C(sp3)ÀH bond. Nevertheless,
the notorious toxicity and carcinogenicity of diazo
compounds, compounded with their explosive be-
Scheme 1. Known CÀH insertion with diazo compounds as commonly employed (top)
havior[10] limits most developments to laboratory
scale with few known industrial applications.[11,12]
and herein reported method (bottom).
While attempting to prepare the iodonium ylide derived
from the simple ketoamide 1a, following a literature procedure
for a similar substrate,[23] we accidentally found that, in THF,
the b-lactam 1b was directly formed in 38% yield (Table 1,
entry 1).
[a] Dr. L. F. R. Gomes, Prof. Dr. C. A. M. Afonso
Instituto de Investigażo do Medicamento (iMed.ULisboa)
Faculty of Pharmacy, University of Lisbon
Av. Prof. Gama Pinto, 1649-019 (Portugal)
E-mail: carlosafonso@ff.ul.pt
This surprising result led us to explore the transformation in
more detail and after a thorough base-, solvent-, and iodane-
screening we settled for the use of NaH as base in THF with
PhI(OAc)2 (Table 1, entries 2–7).[24] The reaction temperature
was found to exert a considerable effect, and carrying out the
reaction at 08C for a certain amount of time followed by rising
to ambient temperature provided the best results. This ena-
bled preparation of the b-lactam 1b in a respectable 68–69%
yield (entries 12 and 13) that was reproducible (71%) on
a larger scale (5-fold increase; Scheme 2).
[b] Prof. Dr. L. F. Veiros
Centro de Quꢀmica Estrutural, Complexo I
Instituto Superior Tꢁcnico, Universidade de Lisboa
Av. Rovisco Pais 1, 1049-001 Lisbon (Portugal)
[c] Prof. Dr. N. Maulide
University of Vienna, Faculty of Chemistry
Institute of Organic Chemistry
Wꢂhringer Strasse 38, 1090 Vienna (Austria)
E-mail: nuno.maulide@univie.ac.at
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201404990.
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were obtained in good yields (up to 75%). The use of unsym-
metrical tertiary amides containing benzylic positions was also
evaluated. As shown, either electron-donating or -withdrawing
groups were tolerated, providing the corresponding b-lactams
5b–8b in moderate yields. Other acyl groups such as alkanoyl
and benzoyl are well tolerated (cf. 10b and 11 b) in this metal-
free CÀH insertion reaction.[25]
Table 1. Selected optimization of conditions for the CÀH insertion.[a]
Entry
Solvent
ArIX2 (X=)
Base[b]
T [8C]/t [h]
Yield [%][b]
At this stage, we became interested in the reaction mecha-
nism. In particular, the possibility of distinguishing between
radical and/or carbene pathways appeared worthy of further
investigation, especially as no informative byproducts could be
isolated during the optimization and substrate scope experi-
ments.[24,26] A particularly elucidative experiment is the at-
tempted insertion onto optically pure, chiral amide 13a. Sin-
glet carbene insertion into CÀH bonds proceeds with full re-
tention of configuration whilst a radical mechanism or triplet
carbene intermediate should afford at least partial racemiza-
tion.[3b] The use of enantiomerically pure 13a (as well as its
enantiomer and meso diastereomer[24]) simplifies the analysis
since, if any racemization occurs, the observed products are
readily identifiable and distinguishable by NMR spectroscopic
analysis. In order to have a suitable standard, the correspond-
ing diazo derivative of 13a and its stereoisomers were synthe-
sized[24] and subjected to Rh2(OAc)4 catalysis under standard
conditions, as it is known that in that case CÀH insertion with
retention of configuration takes place.[28] In the event, this
iodine-mediated transformation displays complete retention of
configuration, supporting a CÀH insertion mechanism by a sin-
glet carbene intermediate (vide infra).
1
2
3
4
5
6
7
11
12
13
THF
OAc
OAc
OAc
OAc
OAc
Otfa
OPiv
OAc
OAc
OAc
NaOMe
KOtBu
KOtBu
KOtBu
NaH
KOtBu
KOtBu
NaH
RT/1
RT/2.2
0/3
0/3.5
0/3
(38)
31
34
41
45
28
38
(53)
(69)
(68)
dioxane
toluene
THF
THF
THF
THF
THF
THF
THF
0/1
0/2
0/1+RT/2
0/0.5+10/2.5
0/0.5+17/2.5
NaH
NaH
[a] Reactions performed using 1a (0.27 mmol), ArIX2 (1.1–1.5 equiv) and
base (2.2–2.7 equiv). [b] Determined by 1H NMR spectroscopy using inter-
nal standard and by isolation (in parentheses). Otfa=trifluoroacetate,
OPiv=pivalate.
As the cyclopropanation of olefins is another reactivity fea-
ture of carbene intermediates,[29] diallylamide 14a was subject-
ed to the optimized conditions. This led to the cyclopropana-
tion product 14b in 39% yield (Scheme 3b), lending further
support to the intermediacy of a carbene.
In addition, a competition experiment with a monodeuterat-
ed substrate 15a was carried out. Since the a-hydrogen of the
final product is labile (active methine), the kinetic isotope
effect (KIE) was calculated based on the nonlabile a-amino-po-
sition (NMR spectroscopic and HRMS analysis, see the Support-
ing Information). The KIE value found was 1.3 with both tech-
niques. This is within recorded experimental values[30] for the
intramolecular insertion with RhII-based catalysts (KIE=1.1–1.6)
into a CÀH bond adjacent to a nitrogen atom and near the
values obtained for CuI catalysis (1.5–3.1). Hence, here the CÀH
insertion is not involved in the rate-determining step of the
overall process. On the other hand, substrate 16a was also
probed to gather additional information. RhII-catalyzed CÀH in-
sertion on the diazo derivative of 16a has been reported to
provide varying relative amounts of b-/g-lactam products for
catalysts with different electronic profiles.[31] In the case of the
transformation described herein, complete selectivity towards
the b-lactam 16b was observed. No g-lactam was observed by
1H NMR spectroscopic analysis of the crude reaction mixture.
Additionally, the mixed substrate 17a was designed to
assess the competition between CÀH insertion and cyclopropa-
nation in our system. As shown, the insertion product 17c was
preferentially formed (Scheme 4). Interestingly, this selectivity
Scheme 2. Scope of the CÀH insertion. DIB=(diacetoxyiodo)benzene;[24]
[a] trans/cis ratio=1:0.2.
With suitable conditions identified for the direct CÀH cycliza-
tion of substrate 1a, a study of the substrate scope was per-
formed (Scheme 2). For amides bearing seven-, six-, and five-
membered rings, the corresponding spiro-b-lactams 2b–4b
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Scheme 6. Free-energy profile (kcalmolÀ1) calculated for the formation of
lactam 1b. The energy values referred to the initial iodonium ylide, A, and
relevant distances are presented (ꢂ).
the intermediate 3a’ were consumed and a signal correspond-
ing to the iodonium ylide 3a’’ was found (found: m/z: 466).
DFT analysis of the reaction mechanism,[32] taking the iodoni-
um ylide as the starting point, provided further insight. The
energy profile obtained for the formation of lactam 1b is de-
picted in Scheme 6.
Scheme 3. Selected set of mechanistic experiments.
in favor of CÀH insertion is in contrast to prior reports employ-
ing RhII catalysis.[18c]
To gain further evidence on reaction intermediates, the reac-
tion progress was followed by mass spectrometry (ESI-LRMS2—
peak deviation Æ1, Scheme 5).[24] The reaction with 3a was se-
lected and an aliquot was taken at the start of the reaction,
which exhibited peaks corresponding to 3a (m/z: 266-main
peak) and the intermediate 3a’ (m/z: 527) that is the precursor
of the iodonium ylide. After approximately 30 min at 08C an-
other aliquot was taken, revealing that the substrate 3a and
The reaction starts with loss of PhI from the iodonium ylide
derived from substrate 1a (A in Scheme 6) resulting in the for-
mation of the corresponding carbene, B/B’. In the transition-
state TSAB, the CÀI bond is practically broken with a distance
of 2.96 ꢂ. This step has an energy barrier of 25 kcalmolÀ1, indi-
cative that carbene formation is the rate-limiting step. Interest-
ingly, the singlet carbene B’ is more stable than its triplet form
by DG=4 kcalmolÀ1. This finding is in agreement with the re-
tention of configuration, without racemization, ob-
served during the CÀH insertion of optically pure
substrate 13a (cf. Scheme 3).
Once formed, carbene B’ overcomes a barrier of
only 5 kcalmolÀ1 and forms the final lactam 1b, in
the second step of the mechanism. The transition-
state TSB’1b is a rather early one with only incipient
CÀC and CÀH bond formation as shown by the long
bond lengths (2.51 and 1.76 ꢂ, respectively).
Through calculation we were also able to compare
b-with g-lactam formation in the case of substrate
16a (see Scheme 3). The overall
Scheme 4. Competition experiment: CÀH insertion versus cyclopropanation.
mechanism obtained[24] is equiv-
alent to the one described
above for 1b, with formation of
free carbene followed by CÀH
insertion with lactam formation.
In this case, carbene formation
has an energy barrier of 23 kcal
molÀ1 and is also the rate-limit-
Scheme 5. Monitoring the reaction of 3a by ESI-LRMS2.[24]
Chem. Eur. J. 2014, 20, 1 – 6 www.chemeurj.org
ing step of the mechanism. The
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[5] K. P. Kornecki, J. F. Briones, V. Boyarskikh, F. Fullilove, J. Autschbach, K. E.
Schrote, K. M. Lancaster, H. M. L. Davies, J. F. Berry, Science 2013, 342,
351.
[6] M. Brookhart, W. B. Studabaker, Chem. Rev. 1987, 87, 411.
[7] M. P. Doyle, R. Duffy, M. Ratnikov, L. Zhou, Chem. Rev. 2010, 110, 704.
[8] A. Padwa, S. F. Hornbuckle, Chem. Rev. 1991, 91, 263.
[9] H. M. L. Davies, R. E. J. Beckwith, Chem. Rev. 2003, 103, 2861.
[10] a) T. Nozoe, T. Asao, M. Yasunami, H. Wakui, T. Suzuki, M. Ando, J. Org.
Chem. 1995, 60, 5919; b) J. R. Fulton, V. K. Aggarwal, J. de Vicente, Eur. J.
Org. Chem. 2005, 1479.
free energy balance for the CÀH insertion step leading to the
two possible lactams is summarized in Scheme 7. Although the
g-lactam E is more stable than its b-isomer by 16 kcalmolÀ1,
[11] a) Y.-S. Huang, W.-Q. Zhang, P.-F. Zhang, X.-G. Liu, Ind. Eng. Chem. Res.
2010, 49, 12164; b) T. N. Salzmann, R. W. Ratcliffe, B. G. Christensen, F. A.
Bouffard, J. Am. Chem. Soc. 1980, 102, 6161; c) J. H. Simpson, J. Godfrey,
R. Fox, A. Kotnis, D. Kacsur, J. Hamm, M. Totelben, V. Rosso, R. Mueller, E.
Delaney, R. P. Deshpande, Tetrahedron: Asymmetry 2003, 14, 3569.
[12] Furthermore, they are usually synthesized through diazo transfer from
sulfonyl azides, themselves potentially explosive reagents: E. D. God-
dard-Borger, R. V. Stick, Org. Lett. 2007, 9, 3797.
Scheme 7. Free-energy balance (kcalmolÀ1) for the CÀH insertion step lead-
ing to either b-lactam (16b, left) or g-lactam (E, right) from the carbene de-
rived from substrate 16a (D’ in the scheme).
[13] T. Horneff, S. Chuprakov, N. Chernyak, V. Gevorgyan, V. V. Fokin, J. Am.
Chem. Soc. 2008, 130, 14972.
[14] a) P. Mꢄller, D. Fernandez, P. Nury, J. C. Rossier, J. Phys. Org. Chem. 1998,
11, 321; b) I. K. Mangion, I. K. Nwamba, M. Shevlin, M. A. Huffman, Org.
Lett. 2009, 11, 3566.
[15] a) R. M. Moriarty, J. Org. Chem. 2005, 70, 2893; b) P. Mꢄller, Acc. Chem.
Res. 2004, 37, 243; c) V. V. Zhdankin, P. J. Stang, Chem. Rev. 2008, 108,
5299.
[16] F. Miege, C. Meyer, J. Cossy, Angew. Chem. Int. Ed. 2011, 50, 5932;
Angew. Chem. 2011, 123, 6054.
the corresponding barrier is 3 kcalmolÀ1 higher, making the b-
lactam 16b the kinetic product of the reaction and the one ex-
perimentally observed.
In conclusion, we report herein a transition metal-free CÀH
insertion of b-ketoamides to directly deliver b-lactam products
in a single step. To the best of our knowledge, this is the first
report of such a direct in situ iodonium ylide formation with
CÀH insertion proceeding without the assistance of a transi-
tion-metal catalyst. Mechanistic analysis is consistent with the
facile formation of a reactive singlet carbene as the limiting
step. This transformation, which amounts to a formal dehydro-
genative coupling, circumvents the classical use of diazo sub-
strates for CÀH insertion chemistry.
[17] E. J. Miller, W. Zhao, J. D. Herr, A. T. Radosevich, Angew. Chem. Int. Ed.
2012, 51, 10605; Angew. Chem. 2012, 124, 10757.
[18] For representative examples, see: a) A. Archambeau, F. Miege, C. Meyer,
J. Cossy, Angew. Chem. Int. Ed. 2012, 51, 11540; Angew. Chem. 2012,
124, 11708; b) S. Chuprakov, J. A. Malik, M. Zibinsky, V. V. Fokin, J. Am.
Chem. Soc. 2011, 133, 10352; c) P. Mꢄller, D. Fernandez, Helv. Chim. Acta
1995, 78, 947; d) M. Ochiai, M. Kunishima, S. Tani, Y. Nagao, J. Am.
Chem. Soc. 1991, 113, 3135.
[19] a) N. R. Candeias, C. Carias, L. F. R. Gomes, V. Andrꢅ, M. T. Duarte, P. M. P.
Gois, C. A. M. Afonso, Adv. Synth. Catal. 2012, 354, 2921; b) N. R. Can-
deias, P. M. P. Gois, C. A. M. Afonso, J. Org. Chem. 2006, 71, 5489; c) I. D.
Jurberg, B. Peng, E. Wostefeld, M. Wasserloos, N. Maulide, Angew. Chem.
Int. Ed. 2012, 51, 1950; Angew. Chem. 2012, 124, 1986.
Acknowledgements
[20] a) C.-J. Li, Acc. Chem. Res. 2009, 42, 335; b) C. J. Scheuermann, Chem.
Asian J. 2010, 5, 436; c) M. Klussmann, D. Sureshkumar, Synthesis 2011,
3, 353; d) C. S. Yeung, V. M. Dong, Chem. Rev. 2011, 111, 1215; e) C.
Zhang, C. Tang, N. Jiao, Chem. Soc. Rev. 2012, 41, 3464; f) S. A. Girard, T.
Knauber, C.-J. Li, Angew. Chem. Int. Ed. 2014, 53, 74; g) Y. Wu, J. Wang, F.
Mao, F. Y. Kwong, Chem. Asian J. 2014, 9, 26.
[21] J. L. Roizen, M. E. Harvey, J. Du Bois, Acc. Chem. Res. 2012, 45, 911.
[22] For the generation of iodonium ylides and their metal-free and metal-
catalyzed decomposition, see: a) K. Miyamoto, M. Suzuki, T. Suefuji, M.
Ochiai, Eur. J. Org. Chem. 2013, 3662; b) B. Moreau, A. B. Charette, J. Am.
Chem. Soc. 2005, 127, 18014; c) P. Mꢄller, C. Bolea, Helv. Chim. Acta
2002, 85, 483. For metal-free reactions, see: d) M. B. Camacho, A. E.
Clark, T. A. Liebrecht, J. P. DeLuca, J. Am. Chem. Soc. 2000, 122, 5210;
e) R. M. Moriarty, S. Tyagi, M. Kinch, Tetrahedron 2010, 66, 5801.
[23] M. Kume, T. Kubota, Y. Iso, Tetrahedron Lett. 1995, 36, 8043.
[24] See the Supporting Information for more details.
L.F.R.G., L.F.V, and C.A.M.A. thank Fundażo para a CiÞncia e Tec-
nologia (SFRH/DB/61220/2009, PTDC/QUI-QUI/119823/2010,
PEst-OE/QUI/UI0100/2013, PEst-OE/SAU/UI4013/2011, REDE/
1518/REM/2005) and the Portuguese NMR Network (IST-UTL
Center) for providing access to the MS and NMR spectroscopic
facilities. We further acknowledge AcÅꢃes Integradas Luso-
Alem¼s (A-14/11) and the Max-Plank Institut fꢄr Kohlenfor-
schung, where parts of this research were carried out, for fi-
nancial support.
Keywords: carbenes · CÀH insertion · iodonium ylides ·
lactams · reaction mechanism
[25] The use of brand new glassware led to no change in the observed
yields and selectivities and the observed contents of Cu and Rh were
below the detection limit (ICP-AES analysis).[24]
[1] M. Regitz, G. Maas in Diazo Compounds; Properties and Synthesis Aca-
demic Press, Orlando, 1986.
[26] Attempted interception by radical
traps or employing radical-clock
[2] a) M. P. Doyle, M. A. McKervey, T. Ye in Modern Catalytic Methods for Or-
ganic Synthesis with Diazo Compounds, Wiley: Interscience, New York,
1998; b) A. F. Trindade, J. A. S. Coelho, C. A. M. Afonso, L. F. Veiros,
P. M. P. Gois, ACS Catal. 2012, 2, 370; c) Z. Zhang, J. Wang, Tetrahedron
2008, 64, 6577; d) P. M. P. Gois, C. A. M. Afonso, Eur. J. Org. Chem. 2004,
3773; e) X. Zhao, Y. Zhang, J. B. Wang, Chem. Commun. 2012, 48, 10162;
f) J. Hansen, H. M. L. Davies, Coord. Chem. Rev. 2008, 252, 545.
[3] a) M. S. Platz, J. Org. Chem. 2014, 79, 2341; b) N. R. Candeias, P. M. P.
Gois, L. F. Veiros, C. A. M. Afonso, J. Org. Chem. 2008, 73, 5926.
[4] S. R. Ovalles, J. H. Hansen, H. M. L. Davies, Org. Lett. 2011, 13, 4284.
probes such as 12a[27] did not allow
the establishment of radical inter-
mediates in this reaction.[24]
[27] M. Newcomb, C. C. Johnson, M. B.
Manek, T. R. Varick, J. Am. Chem. Soc.
1992, 114, 10915.
[28] D. F. Taber, E. H. Petty, K. Raman, J. Am. Chem. Soc. 1985, 107, 196.
[29] X. Xu, H. J. Lu, J. V. Ruppel, X. Cui, S. L. de Mesa, L. Wojtas, X. P. Zhang, J.
Am. Chem. Soc. 2011, 133, 15292.
&
&
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[30] G. A. Sulikowski, S. Lee, Tetrahedron Lett. 1999, 40, 8035.
count of the computational details and the corresponding list of refer-
ences are provided as Supporting Information.
[31] A. Padwa, D. J. Austin, A. T. Price, M. A. Semones, M. P. Doyle, M. N. Pro-
topopova, W. R. Winchester, A. Tran, J. Am. Chem. Soc. 1993, 115, 8669.
[32] a) R. G. Parr, W. Yang in Density Functional Theory of Atoms and Mole-
cules, Oxford University Press, New York, 1989; b) DFT/M06–2X calcula-
tions were performed using the gaussian 09 package. A complete ac-
Received: August 25, 2014
Published online on && &&, 0000
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COMMUNICATION
&
Organic Chemistry
L. F. R. Gomes, L. F. Veiros, N. Maulide,*
C. A. M. Afonso*
&& – &&
Metal-free carbene: Treatment of
ucts by an iodonium ylide. Mechanistic
analysis established the intermediacy of
a singlet carbene with unique reactivity
and selectivity (see scheme).
simple b-ketoamides with (diacetoxy-
iodo)benzene in the presence of a base
at 08C directly provides b-lactam prod-
Diazo- and Transition-Metal-Free CÀH
Insertion: A Direct Synthesis of b-
Lactams
For a long time, diazo derivatives have been used…
…for the generation of metal carbenoids and further
CÀH insertion reactions even though they are toxic and
explosive. In their Communication on page &&ff., N.
Maulide, C. A. M. Afonso, and co-workers describe the
use of a common iodide source to allow the formation
of known iodonium ylides. Their in situ decomposition
affords the CÀH-insertion b-lactam product. In the
picture, Prince Henry holds the crucial, glowing ylide
intermediate and leads the brave sailors about to
depart in search for uncharted land (monument to the
Age of Discoveries in Lisbon, Portugal)
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