Mechanism of the rhodium(III)-catalyzed arylation of imines via C-H bond functionalization: Inhibition by substrate

Article abstract of DOI:10.1021/ja211110h

Rh(III)-catalyzed arylation of imines provides a new method for C-C bond formation while simultaneously introducing an α-branched amine as a functional group. This detailed mechanistic study provides insights for the rational future development of this ne

Full text of DOI:10.1021/ja211110h

Communication
pubs.acs.org/JACS
Mechanism of the Rhodium(III)-Catalyzed Arylation of Imines via C−
H Bond Functionalization: Inhibition by Substrate
Michael E. Tauchert,† Christopher D. Incarvito,† Arnold L. Rheingold,‡ Robert G. Bergman,*,§
and Jonathan A. Ellman*,†
†Department of Chemistry, Yale University, New Haven, Connecticut 06520, United States
‡Department of Chemistry, University of CaliforniaSan Diego, La Jolla, California 92093, United States
§Division of Chemical Sciences, Lawrence Berkeley National Laboratory, and Department of Chemistry, University of California,
Berkeley, California 94720, United States
S
* Supporting Information
For our mechanistic investigations, we first studied the
ABSTRACT: Rh(III)-catalyzed arylation of imines provides
a new method for C−C bond formation while simultaneously
introducing an α-branched amine as a functional group. This
detailed mechanistic study provides insights for the rational
future development of this new reaction. Relevant interme-
diate Rh(III) complexes have been isolated and characterized,
and their reactivities in stoichiometric reactions with relevant
substrates have been monitored. The reaction was found to
be first order in the catalyst resting state and inverse first
order in the C−H activation substrate.
arylation of N-protected aromatic imines bearing N-tosyl, N-
Boc, and N-isopropoxycarbonyl protecting groups with 2-
phenylpyridine (2) (Table 1). A considerably higher yield of
a
Table 1. Protecting Groups in Imine Arylation
entry
1
PG
X
product
% yield
rylations of alkenes and alkynes have been well explored in
Ts
H
1a
1b
1b
1c
1d
402a
552a
822a
952a
81
A
the area of chelation-controlled Rh-catalyzed C−H bond
functionalization.1 Our groups and the Shi group recently
extended the scope of such reactions to Rh(III)-catalyzed
arylation of imines (Scheme 1).2 This transformation provides a
b
2
Boc
Boc
Boc
H
3
4
5
H
CF3
H
C(O)OiPr
a
0.05 mmol of 3, 0.10 mmol of 2, 5.0 μmol of [Cp*RhCl2]2, 0.02
Scheme 1. Rh(III)-Catalyzed Imine Arylation
b
mmol of AgSbF6, 0.70 mL of CH2Cl2, T = 75 °C, t = 16 h. 0.05 mmol
of 2.
Boc-amine 1a was observed when a 2-fold excess of 2 relative to
imine 3a was employed (entries 2 and 3).2a
In addition to previously reported transformations using N-
Boc- and N-tosyl-protected imines,2a isopropoxycarbonyl was
included as a protecting group to provide a model substrate for
our kinetic analysis of the reaction. This was necessary because
kinetic study employing N-tosylimines would provide only
limited information as a result of the reversibility of C−C bond
formation and an unfavorable equilibrium between the
substrate and product.2a On the other hand, while the reaction
with N-Boc-protected imine 3b is not reversible,2a competitive
deprotection of the Boc group under the slightly acidic reaction
conditions complicates the kinetic analysis. The N-isopropoxy-
carbonylimine functionality in 3d is comparably electrophlic to
the N-Boc imine and gives similar yields (82 vs 81%) but is
stable toward acids. Importantly, no back reaction to 2 or 3d was
observed when N-isopropoxycarbonylamine 1d was treated with
convenient synthesis of α-branched amines with simultaneous
C−C bond formation. The reaction can be conducted under
mild conditions and displays excellent functional group
compatibility.2 Further advances in this field include the
arylation of other polarized C−X multiple bonds such as
aldehydes,3 isocyanates,4 isonitriles,5 and CO.6
While the mechanism of chelation-controlled Rh(III) catalysis
assisted by acetate has been explored,7 only limited information
is available for the arylation of imines employing either [Cp*Rh-
(MeCN)3][SbF6]2 or a mixture of [Cp*RhCl2]2 and AgSbF6 as
a catalyst. Herein we report an investigation of the mechanistic
steps of the reaction from catalyst initiation to C−C bond
formation and subsequent catalyst propagation (product
release). Relevant intermediates were isolated and characterized
by X-ray diffraction (XRD). In an unusual finding, the rate law
for the reaction revealed substrate inhibition of the catalyst.
Received: November 27, 2011
Published: January 17, 2012
© 2012 American Chemical Society
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Communication
Scheme 2. Irreversibility of C−C Bond Formation
Scheme 4. Alternative Access to Resting State 5
20 mol % of Rh(III) catalyst (Scheme 2). However, quantitative
formation (with respect to Rh) of complex 4d was observed.
Our first objective was to gain insight regarding the nature of
the catalytic species and which reagents are involved in its
formation. To address this issue, we heated 2, [Cp*RhCl2]2,
and AgSbF6 (6:1:4) in CH2Cl2 to 75 °C for 16 h (Scheme 3).
To investigate the C−C bond-formation step of imine
arylation, we monitored the reaction of a 1:2 mixture of 5 and
imine 3d in CD2Cl2 at room temperature (Scheme 5). Initial
Scheme 5. Resting States during Imine Arylation
Scheme 3. Cyclometalation
We observed the formation of a mixture of cyclometalated Rh
complex 5, pyridinium salt 6, and AgCl.8 The mixture exhibited
1
broadened resonances in the H NMR spectra indicative of
ligand exchange with 2. From a concentrated solution of 5 and
6 in CHCl3, single crystals of 5 suitable for XRD analysis were
obtained (Figure 1). Cp* complex 5 has a three-legged piano
formation of imine adduct complex 8d was observed, and this
material was consumed almost completely within 20 h in favor
of 4d with concomitant formation of amine 1d.14
We next developed an independent synthesis of complexes
4a, 4c, and 4d by adding CH2Cl2 solutions of the respective
imines to a mixture of AgSbF6 and 7 at room temperature
(Scheme 6).15 After crystallization, complexes 4a, 4c, and 4d
Scheme 6. C−C Bond Formation and Propagation
Figure 1. Thermal ellipsoid plots of (left) 5 and (right) 4d depicted at
the 50% probability level. H atoms and SbF6 anions have been omitted
for clarity.9,10
stool configuration, with one 2-phenylpyridine acting as a
bidentate κC,κN ligand and the other saturating the free valence
site of the Rh center as a monodentate κN ligand.
Cyclometalation of 2 could also be performed at room
temperature. Presumably, during cyclometalation of [Cp*RhCl2]2
with 2, one molecule of 2 acts as a base in a concerted
metalation−deprotonation (CMD)-type mechanism11 similar
to the acetate-assisted mechanism described by Jones et al.7a
Quantitative separation of 5 from 6 proved difficult, and only
moderate yields of 5 could be obtained. Therefore, we sought
an alternative preparative route to 5. Complex 7, which is
readily available by cyclometalation of [Cp*RhCl2]2 with 2 in
the presence of NaOAc,12 served as a convenient precursor and
afforded 5 in 99% yield by chloride abstraction with AgSbF6 in
the presence of excess 2 (Scheme 4).13 In CH2Cl2 solution,
decomposition of 5 began to occur within a few hours at room
temperature, whereas no decomposition was observed in a
solution containing excess 2.
were obtained in 73, 81, and 66% yield, respectively. These
materials were stable in CD2Cl2 for several days.
We were able to obtain single crystals of 4a, 4c, and 4d suitable
for XRD analysis by slow diffusion of n-pentane into a saturated
solution of the respective compounds in CH2Cl2. The solid-state
structure of Cp* complex 4d (Figure 1) exhibits a three-legged
piano stool configuration, with the deprotonated amine 1d acting
as a tridentate ligand that coordinates to the Rh center via its two
N atoms and the carbonyl oxygen of the protecting group.
To gain further insight into the catalyst propagation step,
complexes 4 were next treated with 2 equiv of the unsubstituted
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Communication
starting material 2. For 4a, the C−H activation complex 5 was
quantitatively generated within 5 h with concomitant release of
the amine product 1a (Scheme 6). Similarly, 4c reacted to give
complex 5 within 30 min and 4d within 1.5 h.
From these stoichiometric transformations (Schemes 5 and
6), we conclude that AgSbF6 and pyridinium salt 6 play
nonessential roles during imine insertion into the Rh−C bond
and during amine release/catalyst propagation, while the 18-
valence-electron (VE) complexes 5 and 4a,c,d represent resting
states of the reaction whose relative amounts depend on the
respective amounts of substrates 2 and 3 and product 1.
We propose a catalytic cycle for the Rh(III)-catalyzed arylation
of imines (Scheme 7) in which the precatalyst mixture of AgSbF6
Figure 2. Monitoring (1H NMR) of the arylation of imine 3d with 2.
Conditions: 0.050 mmol of 3d, 0.300 mmol of 2, 0.050 mmol of
C6Me6 (as internal NMR standard), 5.6 μmol of 5, 0.70 mL of DCE,
T = 75 °C. Black lines (simulated): [3d]t = [3d]0e−kt (k = 0.24 h−1)
and [1d]t = [3d]0(1 − e−kt) (k = 0.28 h−1).
Scheme 7. Proposed Mechanistic Cycle
a
Table 2. Reaction Rates
b
−1
entry
[Rh]
additive (mol %)
k
(h )
0.24
krel
c
c
c
c
c
c
1
2
3
4
5
6
7
5
5
5
5
5
5
none
1.00
1.13
1.30
1.48
1.05
1.36
1.20
6 (5)
0.27
0.31
0.35
0.25
0.32
0.28
6 (10)
6 (20)
6 (40)
AgSbF6 (12)
AgSbF6 (23)
d
[Cp*RhCl2]2
a
0.05 mmol of 1d, 3.00 mmol of 2, 0.05 mmol of C6Me6, DCE (total
b
volume 0.70 mL), T = 75 °C. Determined from logarithmic plots
over the first 5−6 h (75−80% conversion) 5.6 μmol. 2.8 μmol.
c
d
all cases. While 20 mol % 6 increased the reaction rate by a
factor of 1.48 (entries 2−4), addition of 40 mol % 6 resulted in
in only a very modest effect (entry 5). Similarly, AgSbF6 also
resulted in only a small increase in the rate (entry 6). These
modest effects on the reaction rate could either result from
direct involvement of 6 or AgSbF6 or be promoted by a change
in the polarity of the medium.
When we employed a 1:4 mixture of [Cp*RhCl2]2 and
AgSbF6 as a catalyst, the reaction maintained first-order kinetics
with k = 0.28 h−1 (Table 2, entry 7), which is very similar to the
rate constant observed when 5 and 6 were employed in a 1:1
ratio (k = 0.31 h−1; entry 3). We consider this observation as
evidence that the precatalyst mixture of [Cp*RhCl2]2 and
AgSbF6 forms 5 and 6 as the catalytically active compounds in
the reaction.
and [Cp*RhCl2]2 rapidly forms resting state 5 and pyridinium salt
6, with 2 acting as a base during CMD. To enter the catalytic cycle,
18-VE complex 5 needs to lose ligand 2, yielding 16-VE complex
9. Addition of imine 3d leads to complex 8d, which is transformed
to 4d by insertion of the C−N double bond into the Rh−C bond.
The catalytic cycle proceeds by coordination of 2 to give
intermediate 10d. Presumably, the amide nitrogen ligand in 10d
acts as a base during CMD, releasing amine 1d with simultaneous
cyclometalation of 2 to regenerate catalyst 9.
However, alternate mechanisms involving cocatalysts such as
pyridinium salt 6 or AgSbF6 are also possible. To determine the
effects of such additives, we decided to conduct a kinetic
analysis of the reaction (1H NMR monitoring) employing
imine 3d as a model substrate (see above). To simplify the
kinetic analysis, a 6-fold excess of 2 relative to 3d was used to
suppress resting state 4d in favor of 5.16 Lastly, we switched
from CH2Cl2 to 1,2-dichloroethane (DCE) to eliminate
complications that might result from monitoring the reaction
above the reaction solution’s boiling point.
To determine the rate law, we monitored the reaction with
various amounts of resting state 5 and substrate 2. The reaction
was found to be first order in 5 and inverse first order in 2.14
We propose the mechanism shown in eqs 1 and 2 for this
overall transformation. Complex 9 is produced in a fast
Figure 2 depicts the consumption of 3d and formation of 1d
over time using 11 mol % 5 as a catalyst. The reaction followed
first-order kinetics with k = 0.24 h−1 for 1d formation (Table 2,
entry 1) and a slightly larger rate constant for 3d consumption
(k = 0.28 h−1). In subsequent runs of the reaction, varying
amounts of 6 were added. The reaction remained first-order in
equilibrium from resting state 5 by dissociation of 2 (eq 1). The
time dependence of [9] is given by the sum of its rates of
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Journal of the American Chemical Society
Communication
fellowship (Ta 733/1-1 and Ta 733/1-2). We thank Dr. John J.
Curley and Dr. Antonio G. DiPasquale for help in X-ray
analysis. The loan of a heating circulator for kinetic experiments
by Dr. Kenneth B. Wiberg is greatly appreciated.
REFERENCES
■
formation from 5 and consumption by reaction with 3d and 2
(eq 3).17 Setting d[9]/dt equal to zero and solving for [9] gives
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(2) (a) Tsai, A. S.; Tauchert, M. E.; Bergman, R. G.; Ellman, J. A.
J. Am. Chem. Soc. 2011, 133, 1248. (b) Li, Y.; Li, B.-J.; Wang, W.-H.;
Huang, W.-P.; Zhang, X.-S.; Chen, K.; Shi, Z.-J. Angew. Chem., Int. Ed.
2011, 50, 2115.
(3) (a) Yang, L.; Correia, C. A.; Li, C.-J. Adv. Synth. Catal. 2011, 353,
1269. (b) Park, J.; Park, E.; Kim, A.; Lee, Y.; Chi, K.-W.; Kwak, J. H.;
Jung, Y. H.; Kim, I. S. Org. Lett. 2011, 13, 4390.
the steady-state concentration (eq 4). We assume that k−1[2]
≫ k2[3d] because stoichiometric transformations (Scheme 6)
indicated that k−1 > k218 and at least a 4-fold excess of 2 relative
to 3d was used in the kinetics studies. Insertion of eq 4 into eq 5
(4) Hesp, K. D.; Bergman, R. G.; Ellman, J. A. J. Am. Chem. Soc.
2011, 133, 11430.
(5) Zhu, C.; Xie, W.; Falck, J. R. Chem.Eur. J. 2011, 17, 12591.
(6) Du, Y.; Hyster, T. K.; Rovis, T. Chem. Commun. 2011, 47, 12074.
(7) (a) Li, L.; Brennessel, W. W.; Jones, W. D. Organometallics 2009,
28, 3492. (b) Stuart, D. R.; Alsabeh, P.; Kuhn, K.; Fagnou, K. J. Am.
Chem. Soc. 2010, 132, 18326. (c) Li, L.; Jiao, Y.; Brennessel, W. W.;
Jones, W. D. Organometallics 2010, 29, 3404. (d) Hyster, T. K.; Rovis,
T. Chem. Sci. 2011, 2, 1606.
(8) In a control experiment using 6 instead of [Cp*RhCl2]2 as a
catalyst for imine arylation, no catalytic activity was observed,
excluding the possibility of a Rh-free, acid-catalyzed mechanism (1.0
equiv of 1c, 1.5 equiv of 2, 0.4 equiv of 6, CH2Cl2, 16 h at 75 °C).
(9) Crystal data for 5: C32H32F6N2RhSb, Mr = 783.26, orthorhombic
space group P212121, T = 100(2) K, a = 13.046(3) Å, b = 13.991(3) Å,
c = 16.446(3) Å, α = β = γ = 90°, V = 3002.0(10) Å3, μ = 1.512 mm−1,
Z = 4, 153584/9171 collected/unique reflns, R1 = 0.02, wR2 = 0.05,
GOF = 1.080.
(10) Crystal data for 4d: C33H38F6N2O2RhSb, Mr = 904.21,
monoclinic space group P21/c, T = 123(2) K, a = 18.8446(9) Å,
b = 9.9469(4) Å, c = 19.9152(9) Å, α = 90°, β = 100.0660(10)°, γ =
90°, V = 3675.5(3) Å3, Z = 4, μ = 1.391 mm−1, 33709/6747 collected/
unique reflns, R1 = 0.02, wR2 = 0.06, GOF = 1.059.
(11) This mechanism is frequently also described as electrophilic
C−H bond activation. Recently, the term CMD has become more
dominant and will be used in this manuscript. For a review, see:
Lapointe, D.; Fagnou, K. Chem. Lett. 2010, 39, 1118.
yields eq 6 as our expression for the rate law. With kobs = 0.060 h−1,
eq 6 produced excellent fits for the observed amine formation
in the catalytic runs with 4−8 equiv of 2.14
In conclusion, we have provided a detailed study of the
mechanism of Rh(III)-catalyzed imine arylation with 2-
phenylpyridine (2). The precatalyst mixture of [Cp*RhCl2]2
and AgSbF6 leads to cyclometalation of 2 to yield resting state 5
and pyridinium salt 6 via a CMD mechanism. After formation
of 5, both AgSbF6 and 6 are not essential for catalysis. While
the basicity of 2 plays an important role during catalyst
initiation (cyclometalation), it also accounts for substrate
inhibition by stabilizing resting state 5. Insertion of imines into
the Rh−C bond affords amide complex 4. Product release from
intermediate 4 occurs simultaneously with cyclometalation with
2, regenerating 5, during which the deprotonated amine ligand
serves as a base during CMD. Thus, only catalyst initiation
benefits from the basicity of 2, while this basicity inhibits
catalyst turnover. In consequence, possible future directions for
imine arylation could include an alternate catalyst initiation,
potentially permitting a broader scope of the arylating
substrate.
(12) (a) Hijazi, A.; Djukic, J. P.; Allouche, L.; de Cian, A.; Pfeffer, M.;
Le Goff, X. F.; Ricard, L. Organometallics 2007, 26, 4180. (b) Li, L.;
Brennessel, W. W.; Jones, W. D. J. Am. Chem. Soc. 2008, 130, 12414.
(13) Both 5 and a 1:1 7/AgSbF6 mixture displayed catalytic activity,
but no imine (3c) arylation was observed when 7 was employed alone.
(14) See the Supporting Information (SI) for detailed information.
(15) In analogy to the transformation in Scheme 6, intermediate
formation of 8d was observed by NMR in the synthesis of 4d.
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental details for syntheses; kinetic experiments; NMR
spectra for all compounds; and crystallographic data (CIF) for
4a, 4c, 4d, and 5. This material is available free of charge via the
Internet at http://pubs.acs.org.
1
(16) Complexes 4d (minor) and 5 (major) were observed by H
NMR spectroscopy during a catalytic transformation employing a 1:1
ratio of 2 and 3d. When the reaction was run with a 4:1 ratio of 2 and
3d as substrates, only 5 could be detected by 1H NMR. Also see ref 14.
(17) Since the formation of 4d is irreversible, subsequent steps
leading to 1d can be omitted in the rate law analysis.
AUTHOR INFORMATION
Corresponding Author
rbergman@berkeley.edu; jonathan.ellman@yale.edu
■
(18) A solution of complex 5 in CD2Cl2 did not display any traces of
9 detectable by 1H NMR spectroscopy at rt. Reaction of 3d with 9 at rt
yielded 8d, which was slowly converted into 4d.
ACKNOWLEDGMENTS
■
This work was supported by the NIH (Grant GM069559 to
J.A.E.) and by the Director, Office of Energy Research, Office
of Basic Energy Sciences, Chemical Sciences Division, U.S.
DOE (Contract DE-AC02-05CH11231 to R.G.B.). M.E.T.
thanks the Deutsche Forschungsgemeinschaft for a research
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