Regiodivergent Iridium(III)-Catalyzed Diamination of Alkenyl Amides with Secondary Amines: Complementary Access to γ- Or δ-Lactams

Article abstract of DOI:10.1021/jacs.7b11455

Alkenyl N-pivaloylhydroxamates undergo an Ir(III)-catalyzed diamination of the alkene with simple exogenous secondary amines under extraordinarily mild reaction conditions. The regioselectivity of the diamination is controlled by the solvent and the electronics of the cyclopentadienyl (Cp^x) ligand on Ir. On the basis of a set of mechanistic experiments, we propose that the relative rates of Ir(V)-nitrenoid formation versus attack on the amido-Ir-coordinated alkene by the exogenous amine determine the outcome of the reaction.

Full text of DOI:10.1021/jacs.7b11455

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Cite This: J. Am. Chem. Soc. XXXX, XXX, XXX−XXX
Regiodivergent Iridium(III)-Catalyzed Diamination of Alkenyl Amides
with Secondary Amines: Complementary Access to γ- or δ‑Lactams
John H. Conway, Jr. and Tomislav Rovis*
Department of Chemistry, Columbia University, New York, New York 10027, United States
S
* Supporting Information
Cu(II)-catalyzed diamination of N-alkoxy alkenyl amides with
O-benzoylhydroxylamines5 (eq 2) and an azidoiodinane.6 Yu7
ABSTRACT: Alkenyl N-pivaloylhydroxamates undergo
(eq 3) and Chemler8 (eq 4) have also recently reported similar
an Ir(III)-catalyzed diamination of the alkene with simple
exogenous secondary amines under extraordinarily mild
reaction conditions. The regioselectivity of the diamination
is controlled by the solvent and the electronics of the
cyclopentadienyl (Cpx) ligand on Ir. On the basis of a set
of mechanistic experiments, we propose that the relative
rates of Ir(V)-nitrenoid formation versus attack on the
amido-Ir-coordinated alkene by the exogenous amine
determine the outcome of the reaction.
Cu(II)-catalyzed alkene diamination reactions using tethered
alkenyl N-oxy amines. In these examples with Pd(II) and
Cu(II), the reactivity is limited to 5-exo and the activating N−O
bond is retained in the product. Blakey has shown that
hypervalent iodine can effect 6-endo cyclizations of alkenyl
sulfonamides with trifluoromethanesulfonimide.9 Herein we
describe two mild Ir(III)-catalyzed alkene diamination methods
utilizing unactivated functionally diverse secondary amines and a
traceless N-pivaloylhydroxamate oxidant (eq 5) that deliver
complementary γ- and δ-lactams. We demonstrate that the two
methods proceed by complementary reaction pathways largely
controlled by the solvent and exogenous additive.
For our initial investigations, we tethered the alkene to an
amine with a three-carbon linker that would result in a favorable
five- or six-membered ring formation. We had previously used
this strategy to enable a challenging Rh(III)-catalyzed allylic C−
H activation.10 Moreover, we were inspired to use an alkene-
tethered N-pivaloylhydroxamate (1) for this reaction because it
has proven to be a versatile and robust oxidizing directing group
for analogous Rh(III)-catalyzed alkene carboamination reac-
tions.11 We felt that in this application they would enable
installation of two distinct nitrogen units across an alkene due to
their orthogonal reactivity versus simple amines. A preliminary
screen of catalysts and exogenous amines revealed that
Cp*Rh(III) complexes are ineffective at promoting this
transformation, but analogous Cp*Ir(III) complexes, previously
demonstrated by Chang to tolerate amines and anilines in C−H
amination,12 are competent catalysts. On the basis of these
initial results, we conscripted N-methylaniline (2a, Table 1) to
be the model amine for our optimization studies.
itrogen-containing molecules are heavily represented
1
Namong FDA-approved drugs,
and thus synthetic
methods that can quickly and efficiently incorporate nitrogen
are greatly desired. Among these methods, catalytic alkene
diamination has proven to be an attractive yet challenging
transformation.2 Intermolecular diamination reactions have
been developed by Shi and others, although these frequently
suffer from limited amine scope or lack of distinction between
the two amines.3 One strategy to address this shortcoming is to
perform diamination reactions wherein one of the amines is
tethered (Scheme 1). Michael has published reports of Pd(II)-
catalyzed alkene diamination using NFSI as the exogenous
nitrogen source (eq 1),4 which was later rendered intermo-
lecular in a report by Muniz.3e More recently, Cu(II) complexes
have proven to be competent diamination catalysts that expand
the scope of the exogenous amine. Wang has described a
̃
Scheme 1. Alkene Diamination
In an examination of solvents (see Supporting Information for
details), we were pleasantly surprised to find that [Cp*IrCl2]2 in
both trifluoroethanol (TFE) and hexafluoroisopropanol (HFIP)
promotes productive catalysis, but with opposite regioselectivity
(entries 1 and 2). Speculating that the increased acidity of HFIP
relative to TFE is the source of regiodivergence, we determined
that removal of the base and lowering of the amine loading
delivers γ-lactam 3aa in good yield and improved regioselectivity
(62%, 14:1 γ:δ, entry 4). On the other hand, the use of Cs2CO3
presents a drastic improvement in regioselectivity for δ-lactam
4aa but is detrimental to the yield (entry 5), a situation that is
rectified with the less basic KHCO3 (entries 6 and 7).
Received: October 27, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/jacs.7b11455
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
a
respectively and >20:1 rr (γ:δ) for both. Next, we investigated
the effect of substitution on the lactam ring, and found that alkyl
substituents at the β-position are compatible with the reaction
(3ba−3da); however, this substitution has little influence on the
stereochemistry of the formation of the adjacent C−N bond,
resulting in poor diastereoselectivity of the reaction. Disappoint-
ingly, we found that α-substitution on the lactam is not well-
tolerated for this regioisomer (vide infra).13
Table 1. Reaction Optimization
b
c
entry
solvent
TFE
additive
yield (%)
rr (γ:δ)
1
2
3
2 equiv CsOPiv
2 equiv CsOPiv
none
57
30
45
1:12
2:1
Next, we turned our attention to the scope of δ-lactams,
shown in Scheme 3, and found that this reaction is tolerant of a
HFIP
HFIP
HFIP
TFE
9:1
d
g
4
none
62
14:1
<1:20
1:7
a
Scheme 3. δ-Lactam Secondary Amine Scope
5
6
2 equiv Cs2CO3
2 equiv KHCO3
45
60
TFE
d
e
f
g
7
TFE/H2O
2 M KHCO3
76
<1:20
a
Conditions: 1a (1.0 equiv, 0.030 mmol, 0.3 M), 2.0 equiv 2a, 2.5 mol
b
% [Cp*IrCl2]2, 21 °C for 18 h. Yield of dominant isomer as
determined by H NMR. Determined by analysis of H NMR of the
c
1
1
d
e
unpurified reaction mixture. 0.12 mmol 1a, 1.2 equiv 2a. 1:1 ratio.
f
g
Concentration in H2O. Isolated yield of dominant isomer.
Ultimately, we found that use of 2 M aqueous KHCO3 as a
cosolvent, coupled with lowering of the amine loading, gives 4aa
in superior yield and regioselectivity (76%, >20:1 δ:γ, entry 7).
With optimized reaction conditions in hand, we examined the
scope of each reaction. With regard to the γ-lactam scope
(Scheme 2), we found that inclusion of substituents on the
a
Scheme 2. γ-Lactam Scope
a
Conditions: 1a (1.0 equiv, 0.12 mmol, 0.3 M), 1.2 equiv 2, 2.5 mol %
b
[Cp*IrCl2]2, 1:1 TFE: 2 M aq KHCO3, 21 °C for 16 h. 5.0 mol %
[Cp*IrCl2]2. 1.5 equiv 1a used.
c
wider scope of amines. Similar to the γ-lactam scope, we found
that a variety of electronically diverse substituents on the aniline
are tolerated (methoxy, fluoro, and bromo), and the
corresponding lactams (4ab−4ad) are delivered in good yield
(69 to 76%) and excellent regioselectivity (all >20:1 δ:γ)
(Scheme 3a). Furthermore, dialkyl amines with a variety of
functional groups are also competent in the reaction (Scheme
3b). N-benzyl and N-dimethoxybenzyl protected amines 2i and
2m were found to couple with 1a productively, giving the
corresponding products 4ai and 4am in moderate yield (57%
and 60%, respectively) and regioselectivity (8.9:1 and 5.5:1,
respectively). Amines 2k and 2l are also converted to the
corresponding products 4ak and 4al in moderate yield (47% and
50%, respectively) and regioselectivity (10:1 for both).
Impressively, amidine-containing piperazine 4aj, derived from
a
Conditions: 1 (1.0 equiv, 0.12 mmol, 0.3 M), 1.2 equiv 2, 2.5 mol %
[Cp*IrCl2]2, HFIP, 21 °C for 16 h.
arene of varying electronics (methoxy, bromo, fluoro, chloro) is
tolerated with reasonable yield and good to excellent
regioselectivity (3ab−3ae). The reaction is tolerant of moderate
steric bulk near the nitrogen as anilines 2e bearing a 2-chloro
group and 2f bearing an N-benzyl group are converted to the
corresponding products 3ae and 3af in 64 and 76% yields
B
DOI: 10.1021/jacs.7b11455
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Journal of the American Chemical Society
Communication
a
the antidepressant amoxapine (2j), is delivered in excellent yield
(79%) and regioselectivity (>20:1).
Scheme 5. Mechanistic Experiments
We subsequently interrogated the effect of substitution on the
lactam ring, but were disappointed to find that unlike in the γ-
lactam scope, β-substituted alkenyl amides 1b−1d did not
engage in productive reactivity. When we tested α-methyl
alkenyl amide 1e under the standard reaction conditions, we
were encouraged to see some of the corresponding lactam 4ea
(Scheme 4a, entry 1), but the reaction is plagued by the
Scheme 4. α-Substituted Lactam Optimization and Scope
a
b
See Supporting Information for reaction details and yields. Urea 5ea
is also observed in approximately 1:1.6 ratio with lactam 4ea when
c
using the standard conditions for δ-lactam formation. Relative
stereochemistry determined by 1H NMR and comparison to the
nondeuterated spectra. See Supporting Information for more details.
Crossover experiments demonstrate that none of the products,
urea, γ-, or δ-lactam, interconvert under the reaction conditions
and are thus not intermediates to each other.15 Considering that
this undesired urea formation involves a migration of the alkyl
chain of 1e onto the amide nitrogen, we postulate that 5ea is
formed via a Lossen rearrangement followed by trapping of the
isocyanate by 2a (Scheme 5a). When the reaction is run in the
absence of catalyst, no product or urea is observed,
demonstrating that this Lossen rearrangement is catalyst-
dependent.16 Therefore, we postulate that this rearrangement
proceeds through an Ir(V) nitrenoid.17 Considering that a
higher ratio of urea to lactam is observed in the γ-lactam reaction
conditions than the δ-lactam conditions, and that δ-lactam
formation is heavily favored over both γ-lactam and urea
formation when using the more electron-poor [CpIr*pCF3Cl2]2,
we posit that in the product-determining step, oxidation of an
Ir(III)-amido complex to an Ir(V)-nitrenoid causes γ-lactam
formation.
To probe whether the exogenous amine is installed by
migratory insertion or reductive elimination from the Ir versus
nucleophilic attack of the carbon, we synthesized alkenyl amide
trans-1a-d1 (Scheme 5b), and subjected it to the complementary
reaction conditions. Under both TFE and HFIP conditions, we
determined that the two nitrogen units add anti across the
double bond.18
On the basis of these results, we propose the following
mechanism (Scheme 6). Active catalyst I coordinates the amide
and alkene of 1 to generate II. From here, hydrogen bonding of
the relatively acidic solvent HFIP to amine 2 slows nucleophilic
attack and enables Ir(V)-nitrenoid III to form. Migratory
insertion of the Ir(V)-nitrenoid onto the alkene closes the
lactam ring and generates Ir(V) bicycle IV. Nucleophilic attack
of 2 then opens the four-membered iridacycle and reduces the
metal to Ir(III), generating V.19 Proto-demetalation generates γ-
a
Conditions: 1e (1.0 equiv, 0.030 mmol, 0.3 M), 1.2 equiv 2a, 2.5 mol
b
% [CpxIrCl2]2, 2.0 equiv CsOPiv, TFE, 21 °C for 16 h. Determined
c
d
by 1H NMR. 5.0 mol %. Isolated yield using 0.12 mmol 1e.
e
Conditions: 1 (1.0 equiv, 0.12 mmol, 0.3 M), 1.2 equiv 2a, 2.5 mol %
[Cp*pCF IrCl2]2, HFIP, 21 °C for 16 h. Yields are of isolated δ-lactam
only. Regioisomeric ratios reported as δ:γ.
3
formation of urea 5ea. Changing the counterion of the catalyst
presents no improvement (entries 2 and 3). However, we found
that use of the more electron-deficient [Cp*pCF3IrCl2]2
suppresses the formation of 5ea (entry 5) and delivers 4ea in
good isolated yield (74%) and excellent regioselectivity (>20:1)
(Scheme 4b).14 α-Substitution also confers a high degree of
diastereoselectivity to the reaction (>20:1). This high
diastereoselectivity is strongly suggestive of a chairlike transition
state for the diastereomer-determining C−N bond formation
between the alkene and 2a. α-Substituted δ-lactams 4fa and 4ga
are also delivered in good yield (67 and 53%, respectively) with
>20:1 rr and dr.
We were puzzled by the formation of significant amounts of
urea 5ea from 1e when 1a leads to little to no urea formation
under both HFIP and TFE reaction conditions. When we
examined 1e in the standard reaction conditions for γ-lactam
synthesis, urea 5ea is predominantly formed (Scheme 5a).
C
DOI: 10.1021/jacs.7b11455
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Journal of the American Chemical Society
Communication
a
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Scheme 6. Proposed Mechanism
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a
For clarity, oxidation states and Lossen rearrangement are omitted,
1a is shown, and OPiv and Cl, when on Ir, are abbreviated as X. See
Scheme 5a for the postulated Lossen rearrangement mechanism.
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lactam 3 and regenerates the active catalyst. Conversely, in
TFE/2 M KHCO3, the basicity of the solvent mollifies hydrogen
bonding to 2 and speeds up nucleophilic attack, allowing seven-
membered iridacycle VI to form. Alternatively, the electron-
deficiency of [Cp*pCF3IrCl2]2 slows down oxidation of the
catalyst to III. Nitrene formation followed by reductive
coupling, or alternatively reductive elimination followed by
oxidative insertion into the N−O bond closes the lactam ring
and generates VII. Protodemetalation generates δ-lactam 4 and
regenerates active catalyst I.
In conclusion, we have described a novel, regiodivergent
alkene diamination reaction that proceeds under mild
conditions, wherein two orthogonal nitrogen units are installed
across the double bond and the choice of solvent and additive
determine the regioselectivity. Investigation of the mechanism
revealed that this reaction can proceed via two distinct pathways,
likely involving Ir nitrenoid intermediates. Efforts at extending
this reactivity are currently underway.
J. Am. Chem. Soc. 2011, 133, 2350. (c) Hyster, T. K.; Knorr, L.; Ward,
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T. R.; Rovis, T. Science 2012, 338, 500. (d) Hyster, T. K.; Rovis, T.
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Chem. Sci. 2015, 6, 254. (f) Semakul, N.; Jackson, K. E.; Paton, R. S.;
Rovis, T. Chem. Sci. 2017, 8, 1015. (g) Piou, T.; Romanov-Michailidis,
F.; Romanova-Michaelides, M.; Jackson, K. E.; Semakul, N.; Taggart, T.
D.; Newell, B. S.; Rithner, C. D.; Paton, R. S.; Rovis, T. J. Am. Chem.
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5904. (b) Kim, H.; Chang, S. ACS Catal. 2015, 5, 6665.
(13) Dialkyl amines participate under these conditions with modest
selectivities for the γ-lactam but proceed in low yields (∼6:1 rr, ∼20%
yield).
(14) [Cp*pCF3IrCl2]2 was found to be incompatible with alkyl amines.
Additionally, we found 4aa to be the major product when this catalyst
was used in HFIP. See Supporting Information for more details.
(15) See Supporting Information for experiment details.
(16) No product was observed when catalyst was omitted in either
HFIP or TFE/2 M KHCO3 conditions.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/jacs.7b11455.
■
S
(17) For a thorough theoretical and experimental examination into
Ir(V)-nitrenoid formation using Cp*Ir(III) complexes, see: Park, Y.;
Heo, J.; Baik, M.-H.; Chang, S. J. Am. Chem. Soc. 2016, 138, 14020.
(18) Widenhoefer has used a similar deuterium-labeling strategy to
determine that a Pd(II)-catalyzed alkene hydroalkylation with a
diketone proceeds through an outer sphere anti-carbometalation
pathway. See: Qian, H.; Widenhoefer, R. A. J. Am. Chem. Soc. 2003,
125, 2056.
(19) Reductive elimination of IV can be envisioned to deliver a
bicyclic acyl aziridine, which one might expect would lead to ring-
opening to deliver one or both of the observed products. However, this
aziridine has never been isolated, has resisted our own attempts at
isolation and cannot account for the effect of catalyst structure on
regioselectivity; see Supporting Information.
Experimental details, characterization data, and NMR
spectra (PDF)
AUTHOR INFORMATION
Corresponding Author
*tr2504@columbia.edu
■
ORCID
Tomislav Rovis: 0000-0001-6287-8669
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We thank NIGMS (GM80442) for support.
■
REFERENCES
■
(1) Vitaku, E.; Smith, D. T.; Njardarson, J. T. J. Med. Chem. 2014, 57,
10257.
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DOI: 10.1021/jacs.7b11455
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX