Rhodium-Catalyzed C=N Bond Formation through a Rebound Hydrolysis Mechanism and Application in β-Lactam Synthesis

Article abstract of DOI:10.1021/acs.orglett.9b01312

A rhodium-catalyzed reaction of N-hydroxyanilines with diazo compounds to produce α-imino esters was developed. Distinct from the commonly accepted 1,2-H transfer for normal X-H insertion reactions, density functional theory calculations indicate that this transformation proceeds via a novel rebound hydrolysis mechanism. Furthermore, a three-component reaction was explored to synthesize highly functionalized β-lactams in good yields and diastereoselectivities.

Full text of DOI:10.1021/acs.orglett.9b01312

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Rhodium-Catalyzed CN Bond Formation through a Rebound
Hydrolysis Mechanism and Application in β‑Lactam Synthesis
Long Chen,†,§ Linxing Zhang,‡,§ Ying Shao,† Guangyang Xu,† Xinhao Zhang,*,‡,¶ Shengbiao Tang,†
and Jiangtao Sun*,†
†Jiangsu Key Laboratory of Advanced Catalytic Materials & Technology, School of Petrochemical Engineering, Changzhou
University, Changzhou 213164, China
‡Lab of Computational Chemistry and Drug Design, State Key Laboratory of Chemical Oncogenomics, Peking University Shenzhen
Graduate School, Shenzhen 518055, China
¶Shenzhen Bay Laboratory, Shenzhen 518055, China
S
* Supporting Information
ABSTRACT: A rhodium-catalyzed reaction of N-hydroxyani-
lines with diazo compounds to produce α-imino esters was
developed. Distinct from the commonly accepted 1,2-H
transfer for normal X−H insertion reactions, density func-
tional theory calculations indicate that this transformation
proceeds via a novel rebound hydrolysis mechanism. Furthermore, a three-component reaction was explored to synthesize
highly functionalized β-lactams in good yields and diastereoselectivities.
Scheme 1. Previous Reports and Our Work
ransition-metal-catalyzed carbene transfer represents a
Tpowerful tool for constructing various carbon−carbon
and carbon−heteroatom bonds in organic synthesis.1 Typi-
cally, the catalytic carbene insertion into X−H bonds (X = N,
O, S, Si, B, etc.), simplified as X−H insertion reactions (XHI),
has been broadly utilized to form C−X bonds.2 The commonly
accepted mechanism for XHI reactions proceeds stepwise (the
Si−H bond and B−H bond insertion reactions generally
undergo a concerted mechanism), namely, the nucleophilic
attack of the heteroatom to electrophilic metal−carbene
provides the key ylide intermediate, which undergoes 1,2-
proton transfer from X to C to form the C−X single bond
(Scheme 1a).
To develop novel metal−carbene mediated transforma-
tions,3 recently, we reported a rhodium-catalyzed selective N2-
alkylation of benzotriazoles with diazo compounds.3b Quan-
tum mechanical calculations disclose that the reaction involves
a 1,3-proton transfer from N1 to C of 1H-benzotriazole to form
N2−C single bond. Herein, we wish to report another novel
formal XHI reaction with an unprecedented reaction
mechanism. We found that the reaction of N-hydroxyaniline
(an amphiphilic nucleophile with O and N nucleophilic
properties4) with rhodium−carbene intermediates produced
imines rather than N−H/O−H insertion products (Scheme
1b). Density functional theory (DFT) calculations indicate
that C−N bonding proceeds through the nucleophilic addition
of nitrogen atom to rhodium carbene. However, the 1,2-proton
transfer from N to C does not occur, but the leaving of
hydroxy anion does occur. This anion conversely abstracts the
hydrogen from nitrogen and releases a molecule of H2O to
form the CN double bond. This addition−leaving−
abstraction process, namely a “rebound hydrolysis” mecha-
nism, is distinct from the common XHI reactions for C−X
single bond formation.
On the other hand, α-imino esters are key building blocks in
organic synthesis with diverse applications.5 Although
numerous methods exist, there are still limitations in preparing
such motifs. Using metal−carbene as key intermediates, in
2005, the Hu group described a rhodium catalyzed three-
Received: April 15, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b01312
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a b
,
component reaction of α-diazoesters, anilines, and azodicar-
boxylates to produce α-imino esters.6 Later, the Doyle group7
reported the preparation of α-imino esters from donor/
acceptor dirhodium carbenes with azides. Just recently, the
Scheme 2. Substrate Scope
Furstner group developed an efficient protocol by catalytic
̈
metathesis of azobenzenes using a half-sandwich rhodium
catalyst under blue LED irradiation.8 Compared with azides
and azobenzenes, N-hydroxyanilines have many advantages
such as stability, safety, and ready availability. We then sought
to test N-hydroxyanilines as the nitrogen sources to prepare α-
imino esters. The initial investigation started from the reaction
of N-hydroxyaniline (1a) with diazoacetate (2a) under
rhodium catalysis at room temperature (Table 1). We found
a
Table 1. Optimization of the Reaction Conditions
b
entry
[Rh]
solvent
time (h)
yield (%)
1
2
3
4
5
6
7
8
[Cp*RhCl2]2
[Rh(COD)Cl]2
Rh2(esp)2
Rh2(OPiv)4
Rh2(Oct)4
Rh2(OAc)4
Rh2(esp)2
Rh2(esp)2
Rh2(esp)2
Rh2(esp)2
Rh2(esp)2
DCM
DCM
DCM
DCM
DCM
DCM
DCE
CHCl3
THF
MeCN
toluene
DMF
0.5
0.5
0.5
0.5
0.5
2
0.5
0.5
0.5
0.5
0.5
0.5
73
trace
94
87
35
94
90
87
84
68
78
83
a
Standard reaction conditions: 1 (0.2 mmol), 2 (0.24 mmol), and
Rh2(esp)2 (1 mol %) in CH2Cl2 (4 mL); the mixture was stirred at rt
b
c
for 30 min. Isolated yields. The reaction was performed at 80 °C for
d
6 h. The reaction was performed at 80 °C for 1 h.
9
10
11
12
drawing groups was tolerated, furnishing the desired imines
(3i−3k) in excellent yields. Other types of diazo compounds
such as dimethyl 2-diazomalonate, enol diazoacetate, α-phenyl
trifluoromethyl, and phosphonate diazos were all amenable to
this reaction, affording the desired products (3m−3p) in good
yields. Notably, the donor−donor diazo compounds also
reacted well, leading to moderate yields of desired imines (3q−
3t).
Rh2(esp)2
a
Standard reaction conditions: 1a (0.2 mmol), 2a (0.24 mmol),
rhodium catalyst (1 mol %), CH2Cl2 (4 mL). The mixture was stirred
at rt. Isolated yields.
b
To better understand the reaction mechanism, DFT
calculations were conducted (Figure 1). The initial processes
should be the formation of active rhodium carbene (INT1)
between Rh2(OAc)4 and 2a (Supplementary Figure 1),
followed by the nucleophilic attack of N atom in 1a to
INT1, which is barrierless and exergonic by 21.0 kcal/mol
(Supplementary Figure 1). Next, the ammonium ylide 1-INT2
undergoes direct decomposition with 9.8 kcal/mol barrier (1-
TS2), giving an iminium/hydroxy ion pair (1-INT3).9 The
geometries show that with the forming of iminium ion, the N−
O bond (1.47 Å in 1-INT2, 1.97 Å in 1-TS2, and 2.05 Å in 1-
INT3) and Rh−C bond (2.35 Å in 1-INT2, 3.05 Å in 1-TS2
and 3.24 Å in 1-INT3) are elongating, indicating the
dissociation of hydroxy anion and Rh2(OAc)4. Finally, the
hydroxy anion rebounds and abstracts the hydrogen in the
iminium ion moiety of 1-INT3 with only 0.3 kcal/mol barrier
(1-TS3) to yield imine 4a.10 For 1-TS3, the distance of O···H
decreases slightly to 1.96 Å, and the geometry is still close to 1-
INT3, which is consistent with Hammond’s postulate.11 Two
other possible pathways involving the commonly proposed N−
H insertion into the Rh carbene were also considered.12 As
shown by the blue line, the ion pair intermediate 1-INT3 may
undergo H2O-catalyzed [1,2]-H shift after the dissociation of
Rh2(OAc)4 via transition state 2-TS3 with 10.0 kcal/mol
barrier and give the N−H insertion product 2-INT4
that the use of 1 mol % of [Cp*RhCl2]2 furnished 3a in 73%
yield (entry 1), whereas [Rh(COD)Cl]2 can not catalyze this
reaction (entry 2). To our delight, the use of Rh2(esp)2 or
Rh2(OAc)4 as the catalyst delivered 3a in 94% yield under very
mild conditions (entries 3 and 6), and longer reaction time was
required for Rh2(OAc)4. Rh2(OPiv)4 also exhibited good
catalytic reactivity, providing 3a in 87% yield (entry 4). In
contrast, Rh2(Oct)4 was less effective and only gave 35% yield
(entry 5). Next, other solvents were screened, and it was found
that DCM still was the best choice (entries 7−12).
With the established optimal reaction conditions, we next
investigated the substrate scope for imine formation (Scheme
2). First, the scope of N-hydroxyanilines (1) was evaluated,
and it was found that N-hydroxyanilines bearing either
electron-donating or electron-withdrawing substituents were
all amenable to the reaction, providing imines (3b−h) in
excellent yields (85−95%). Typically, the sterically hindered
imine 3h, which could not be obtained via catalytic metathesis
of azobenzene,7 was obtained in 85% yield via this approach.
For the scope of diazo compounds, the phenyl ring of the diazo
substrates bearing either electron-donating or electron-with-
B
DOI: 10.1021/acs.orglett.9b01312
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Figure 1. Free energy profile of dirhodium(II) complex catalyzed CN bond formation. Free energies and enthalpies (in parentheses) are given in
kcal/mol; atomic distances are in Å.
irreversibly.13 Furthermore, the elimination of H2O from 2-
INT4 to produce 4a requires 40.4 kcal/mol (2-TS4), which is
energetically infeasible at room temperature. As shown by the
red line, the ammonium ylide 1-INT2 may transform into the
enol 3-INT3 via H2O-catalyzed [1,4]-H shift (3-TS2) and is
endergonic by 12.1 kcal/mol. The following H2O-catalyzed
[1,3]-H shift of 3-INT3 with 9.2 kcal/mol barrier (3-TS3)
leads to the N−H insertion product 2-INT4.14 Both of two
N−H insertion pathways were calculated to have higher energy
barriers than the rebound hydrolysis mechanism.
Scheme 4. Substrate Scope for Rhodium-Catalyzed Lactam
a b
,
Formation
Next, following Doyle’s procedure,7 the one-pot reaction of
N-hydroxyaniline 1a and diazoaceate 2a and 4a to synthesize
β-lactam was examined. We found that Rh2(esp)2 cannot
achieve the Staudinger cyclization; thus, Rh2(OAc)4 (1 mol %)
was used and delivered lactam 5a in 83% yield with excellent
diastereoselectivity (>20:1 dr) (Scheme 3). The reaction
Scheme 3. Rhodium-Catalyzed β-Lactam Formation
a
Reactions were carried out with 1 (0.2 mmol), 2 (0.24 mmol), 4
(0.36 mmol), and Rh2(OAc)4 (1 mol %) in CH2Cl2 (4 mL) at rt for 3
b
c
d
h. Isolated yields. 80 °C for 2 h. 80 °C for 7 h.
involves the rhodium-catalyzed imine formation and Wolff
rearrangement15 to afford imine and ketene intermediates,
respectively. Then, the thermal Staudinger cyclization16 of
imine with ketene occurs to form lactam 5a.
We next extended this three-component reaction to a range
of substrates (Scheme 4). First, the scope of aniline has been
examined, and we found the anilines containing various
electron-donating and electron-withdrawing groups were all
tolerated in this reaction, providing the corresponding β-
lactams (5a−5h) in good yields with excellent dr ratio
(>20:1). Next, the scope of diazo substrates 2 was evaluated.
We found that various donor−acceptor diazo compounds were
tolerated, affording the desired lactams in good yields (5i−5o).
Acceptor−acceptor diazo compound was also amenable to the
reaction and afforded 5p in 52% yield. Then, the scope of
diazo compounds 4 for the ketene formation was finally
disclosed, and the corresponding lactams were isolated in
C
DOI: 10.1021/acs.orglett.9b01312
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
57, 12489. (c) Xu, G.; Chen, P.; Liu, P.; Tang, S.; Zhang, X.; Sun, J.
Angew. Chem., Int. Ed. 2019, 58, 1980.
moderate yields (5q−5s). The structures of 5q and 5s were
determined by X-ray diffraction.
(4) (a) Wang, Y.; Ye, L.; Zhang, L. Chem. Commun. 2011, 47, 7815.
(b) Wang, Y.; Liu, L.; Zhang, L. Chem. Sci. 2013, 4, 739. (c) Chen, J.-
M.; Chang, C.-J.; Ke, Y.-J.; Liu, R.-S. J. Org. Chem. 2014, 79, 4306.
(d) Huple, D. B.; Mokar, B. D.; Liu, R.-S. Angew. Chem., Int. Ed. 2015,
54, 14924. (e) Mokar, B. D.; Huple, D. B.; Liu, R.-S. Angew. Chem.,
Int. Ed. 2016, 55, 11892. (f) Raj, A. S. K.; Kale, B. S.; Mokar, B. D.;
Liu, R.-S. Org. Lett. 2017, 19, 5340. (g) Hsu, Y.-C.; Hsieh, S.-A.; Li,
P.-H.; Liu, R.-S. Chem. Commun. 2018, 54, 2114.
(5) Eftekhari-Sis, B.; Zirak, M. Chem. Rev. 2017, 117, 8326.
(6) Huang, H.; Wang, Y.; Chen, Z.; Hu, W. Adv. Synth. Catal. 2005,
347, 531.
(7) Mandler, M. D.; Truong, P. M.; Zavalij, P. Y.; Doyle, M. P. Org.
Lett. 2014, 16, 740 and references therein .
In summary, we demonstrated a novel rhodium-catalyzed
CN bond formation from the reaction of N-hydroxyanilines
with carbene precursors. DFT calculations indicate that this
transformation occurs through a “rebound hydrolysis”
mechanism. Moreover, based on the novel imine formation,
a three-component reaction to prepare fully substituted β-
lactams was developed. The reaction proceeds through
rhodium-catalyzed imine formation, Wolff rearrangement,
and Staudinger reaction to deliver the final products in high
efficiency.
ASSOCIATED CONTENT
■
́
̀
(8) Tindall, D. J.; Werle, C.; Goddard, R.; Philipps, P.; Fares, C.;
Furstner, A. J. Am. Chem. Soc. 2018, 140, 1884.
S
* Supporting Information
̈
(9) For selected examples on the iminium ion pair, see: (a) Cametti,
M.; Nissinen, M.; Dalla Cort, A.; Mandolini, L.; Rissanen, K. J. Am.
Chem. Soc. 2007, 129, 3641. (b) Khomutova, Y. A.; Smirnov, V. O.;
Mayr, H.; Ioffe, S. L. J. Org. Chem. 2007, 72, 9134. (c) Zuend, S. J.;
Jacobsen, E. N. J. Am. Chem. Soc. 2009, 131, 15358. (d) Moran, A.;
Hamilton, A.; Bo, C.; Melchiorre, P. J. Am. Chem. Soc. 2013, 135,
9091. (e) Hermeke, J.; Mewald, M.; Oestreich, M. J. Am. Chem. Soc.
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b01312.
Experimental procedures, characterizing data, and copies
of NMR spectra (PDF)
Accession Codes
́
́
́
2013, 135, 17537. (f) Calleja, J.; Gonzalez-Perez, A. B.; de Lera, A. R.;
́
́
Alvarez, R.; Fananas, F. J.; Rodríguez, F. Chem. Sci. 2014, 5, 996.
̃
CCDC 1860109−1860110 contain the supplementary crys-
tallographic data for this paper. These data can be obtained
free of charge via www.ccdc.cam.ac.uk/data_request/cif, or
emailing data_request@ccdc.cam.ac.uk, or by contacting The
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
(10) For examples on the rebound mechanism: (a) Groves, J. T. J.
Chem. Educ. 1985, 62, 928. (b) Mahapatra, S.; Halfen, J. A.; Tolman,
̈
W. B. J. Am. Chem. Soc. 1996, 118, 11575. (c) Schoneboom, J. C.;
Cohen, S.; Lin, H.; Shaik, S.; Thiel, W. J. Am. Chem. Soc. 2004, 126,
4017. (d) Shaik, S.; Kumar, D.; de Visser, S. P.; Altun, A.; Thiel, W.
Chem. Rev. 2005, 105, 2279. (e) Haines, B. E.; Nelson, B. M.;
Grandner, J. M.; Kim, J.; Houk, K. N.; Movassaghi, M.; Musaev, D. G.
J. Am. Chem. Soc. 2018, 140, 13375.
AUTHOR INFORMATION
Corresponding Authors
■
(11) Hammond, G. S. J. Am. Chem. Soc. 1955, 77, 334.
(12) (a) Xu, B.; Zhu, S.-F.; Xie, X.-L.; Shen, J.-J.; Zhou, Q.-L. Angew.
Chem., Int. Ed. 2011, 50, 11483. (b) Wang, X.-C.; Song, X.-S.; Guo,
L.-P.; Qu, D.; Xie, Z.-Z.; Verpoort, F.; Cao, J. Organometallics 2014,
33, 4042. (c) Kisan, H. K.; Sunoj, R. B. Chem. Commun. 2014, 50,
14639. (d) Jindal, G.; Kisan, H. K.; Sunoj, R. B. ACS Catal. 2015, 5,
480.
(13) Liang, Y.; Zhou, H.; Yu, Z.-X. J. Am. Chem. Soc. 2009, 131,
17783.
(14) Xie, Z.-Z.; Liao, W.-J.; Cao, J.; Guo, L.-P.; Verpoort, F.; Fang,
W. Organometallics 2014, 33, 2448.
(15) For a review, see: (a) Kirmse, W. Eur. J. Org. Chem. 2002, 2002,
2193. For selected recent examples on Wolff rearrangement, see:
(b) Rodriguez, K. X.; Kaltwasser, N.; Toni, T. A.; Ashfeld, B. L. Org.
Lett. 2017, 19, 2482. (c) Hu, X.; Chen, F.; Deng, Y.; Jiang, H.; Zeng,
W. Org. Lett. 2018, 20, 6140.
(16) (a) France, S.; Weatherwax, A.; Taggi, A. E.; Lectka, T. Acc.
Chem. Res. 2004, 37, 592. (b) Tuba, R. Org. Biomol. Chem. 2013, 11,
5976. (c) Cossío, F. P.; Arrieta, A.; Sierra, M. A. Acc. Chem. Res. 2008,
41, 925. (d) Fu, N.; Tidwell, T. T. Tetrahedron 2008, 64, 10465.
(e) Jiao, L.; Liang, Y.; Xu, J. J. Am. Chem. Soc. 2006, 128, 6060.
*E-mail: zhangxinhao@pku.edu.cn.
*E-mail: jtsun08@gmail.com or jtsun@cczu.edu.cn.
ORCID
Ying Shao: 0000-0002-7379-8266
Xinhao Zhang: 0000-0002-8210-2531
Jiangtao Sun: 0000-0003-2516-3466
Author Contributions
§L.C. and L.Z. contributed equally to this work
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the NSFC (Grants 21572024 and 21572192),
Shenzhen STIC (Grant JCYJ20170412150343516), and
Jiangsu Key Laboratory of Advanced Catalytic Materials &
Technology (Grant BM2012110).
REFERENCES
■
(1) For selected reviews, see: (a) Davies, H. M. L.; Hedley, S. J.
Chem. Soc. Rev. 2007, 36, 1109. (b) Doyle, M. P.; Duffy, R.; Ratnikov,
M.; Zhou, L. Chem. Rev. 2010, 110, 704. (c) Xia, Y.; Qiu, D.; Wang, J.
Chem. Rev. 2017, 117, 13810. (d) Cheng, Q.-Q.; Deng, Y.; Lankelma,
M.; Doyle, M. P. Chem. Soc. Rev. 2017, 46, 5425. (e) Zhang, D.; Hu,
W. Chem. Rec. 2017, 17, 739.
(2) For selected reviews, see: (a) Zhu, S.-F.; Zhou, Q.-L. Acc. Chem.
Res. 2012, 45, 1365. (b) Gillingham, D.; Fei, N. Chem. Soc. Rev. 2013,
42, 4918. (c) Ren, Y.-Y.; Zhu, S.-F.; Zhou, Q.-L. Org. Biomol. Chem.
2018, 16, 3087.
(3) (a) Liu, K.; Xu, G.; Sun, J. Chem. Sci. 2018, 9, 634. (b) Wang, K.;
Chen, P.; Ji, D.; Zhang, X.; Xu, G.; Sun, J. Angew. Chem., Int. Ed. 2018,
D
DOI: 10.1021/acs.orglett.9b01312
Org. Lett. XXXX, XXX, XXX−XXX