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MECHANISM OF THE WEEK

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SYNERGISTIC CATALYSIS IN
RHODIUM CARBENE
CHEMISTRY
A Review Prepared by Arianne Hunter*, Kiran Chinthapally,
Ibikari Legg-Jack, and Indrajeet Sharma to be submitted to
Organic and Biomolecular Chemistry

February 2nd, 2019
What is synergistic
catalysis? No Catalysis Traditional Catalysis Synergistic Catalysis
δ+ δ+
LUMO E LUMO E LUMO E
δ+

[E – cat]δ+
• A mode of catalysis in which two [E – cat]δ+

catalysts and two catalytic cycles ΔE
ΔE ΔE
cooperatively work to create a new [Nu – cat]δ-

single bond HOMO
Nu δ-
HOMO
Nu δ- Nu δ-
HOMO
Nu δ-
altering the energy of a a simultaneous or tandem
single component in the
• Enables transformations that are reaction system
change in the energy of
both reacting components

usually impossible or inefficient using
traditional monocatalytic systems Figure 1: In synergistic catalysis both the HOMO and the LUMO of
the reacting system are concurrently activated using distinct
• Less explored due to difficulty in catalysts creating two catalytic cycles that must work togeter
ensuring redox compatibility of metals

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Rh(II) carbenes in R2
O
R1
O
R2 Cat.
R1
O
R2

synergistic catalysis R1
N2
Rh2L4
Nu

E
H Nu E

O
insertion
R2
• Diazo derived Rh(II) carbenes are Rh22L
Rh L44
byproduct – Rh2L4
R1 O
attractive partners in synergistic H R1 R2 R1
O – Cat.

H R2
transformations Nu
Nu Rh2L4 Cat.
H
Rh2L4
Nu
E
E zwitterionic
• Ease of formation Intermediate
E Cat.

• Relative stability Advantages Challenges
• Controlled reactivity in typical - efficient and selective
- high atom economy
- stabilization of intermediates
- identification of compatible
catalytic reactions - enables new transformations substrates/catalysts

• Redox compatibility with a variety of
transition metals
Figure 2: General mechanism for Rh(II) carbenes in synergistic
catalytic cycles

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WHAT WILL Trapping Zwitterionic
Intermediates With The
Following Electrophilic
THIS REVIEW Species:

COVER?
1. Carbonyls and iminium ions
2. Michael acceptors
3. Gold-activated alkynes
4. π-allyl Pd(II) complexes

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1) Trapping With Aldehydes Using Rh(II) and Lewis Acids:
Synthesis of Dihydroxy Acid Frameworks
major minor I I
a) BnO H Rh2(OAc)4 (1 mol%) OBn OBn 1
CO2Me 2 (1.2 eq) Zr(IV)–S-BINOL (15 mol%) MeO2C Ar1 MeO2C Ar O O
+ Zr
+ DCE, 0 ºC, 3-4 hr
N2 O O
Ar1 Ar2 O Ar2 OH Ar2 H
1 (1 eq) H OH
3 (1.1 eq) I I
erythro – 4 threo – 4
5, Zr(IV)–S-BINOL

c) Proposed Mechanism CO2Me
Zr(IV)/BINOL Ar1
b) Representative Examples O N2
Rh2(OAc)4 1
– N2
OBn OBn OBn Ar2
MeO2C Ph MeO2C Ph MeO2C Ph –Zr(IV)/BINOL
MeO2C
“delayed proton Ar1 CO2Me
OBn
transfer”
Ph OH p-MeOPh OH p-NO2Ph OH 1
H H H OH H 9 Rh2(OAc)4 6 Ar
4a, 81% (dr = 9:1) 4b, 68% (dr = 8:2) 4c, 43% (dr = 7:3)
ee = 98% Ar2
ee = 96% ee = 60% MeO2C
Ar1 BnO–H
OBn
CO2Me 2
4 Rh2(OAc)4
Zr(IV)/BINOL Ar1
O
δ+ CO2Me
O H OBn – Rh2(OAc)4 H
7 Ar1
Ar2 protodemetalation OBn
Ar2 8
X. Zhang, H. Huang, X. Guo, X. Guan, L. Yang and W. Hu, Angew. 3 3 - Zr observed when aldehyde is
Chem. Int. Ed. Engl., 2008, 47, 6647–6649. unactivated6
1) Trapping With Aldehydes Using Rh(II) and Lewis Acids:
Synthesis of β-hydroxyl-α-amino Acid Derivatives
Cocatalyst Yield
In (15 mol%) (%)
CbzNH2 Rh
O H NHCbz
a) CO2Me 10 (1 eq) O Cu(OTf)2 0
+ Rh2(OAc)4 (1 mol%) N MeO2C Ar1 Zn(OTf)2 50
N2 Ar 1 InCl3 (15 mol%) MeO Cbz Yb(OTf)3 24
O 2 H In(OTf)3 50
2 Ar
1 (1.9 eq) Ar CH2Cl2, rt, 1 hr Ar2 H InCl3 55
Ar1 OH
3 (1.2 eq) 11 favored “none” 0
anti – 12
transition state Ar2 = p-NO2Ph

b) Representative Examples
NHCbz NHCbz NHCbz
MeO C MeO2C NHCbz
MeO2C Ar1 2 Ar1 Ar1 MeO2C Ar1

Ph H p-MeOPh H o-NO2Ph H Ph H
OH OH OH OH
12a, 60% 12b, 39% 12c, 75% 12d, 62%
dr = 20:1 dr = 20:1 dr = 20:1 dr = 6:4

J.-B. Xi, M.-L. Ma and W. Hu, Tetrahedron, 2016, 72, 579–583.
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2) Trapping With Imines Using Rh(II) and Chiral Phosphoric Acids:
Enantioselective Access to Oxindole Scaffolds
a) Ar2
R2 Ar1
O Ar1 Rh2(OAc)4 (2 mol%) N
R2 N H
*PPA1 H (10 mol%) O
N +
R1 N2 Ar2 CH2Cl2, -20 ºC, 2 hr N
13 (2 eq) 14 (1 eq) 15 R1
SiPh3

R2 O O
H Ar1 P
O *PPA1 N O OH
N Rh +
R 1 Ar2 SiPh3
16
zwitterionic 14 - PPA 17 *PPA1 H
intermediate

b) Representative Examples
Ph p-ClPh Ph p-ClPh Ph p-CF Ph p-BrPh
Et H Et 3 Ph
N Et
N N N
When *PPA–H is not present, reaction H H H
O O H
proceeds but with moderate d.r. and 0% ee O O
N N N N
Me Me Me Et
15a, 77% (dr = 98:2) 15b, 70% (dr = 9:1) 15c, 57% (dr = 99:1) 15d, 70% (dr = 98:2)
ee = 96% ee = 83% ee = 95% ee = 88%

H. Qiu, M. Li, L. Q. Jiang, F. P. Lv, L. Zan, C. W. Zhai, M. P.
Doyle and W. H. Hu, Nat Chem, 2012, 4, 733-738. 8
2) Trapping With Imines Using Rh(II) and Chiral Phosphoric Acids:
α,α-Diaryl All-Carbon Benzylic Quaternary Stereocenters

R

a)
CO2Me R1 O O
R1
Rh2(OAc)4 (2 mol%) P
N N2 Ph N Ar1 O OH
R2 *PPA2 H (10 mol%) R2 NH
1 (1 eq) 1
N Ar CH Cl , 0 ºC, 1.5 hr
H 2 2 Ar2 R
Ar2 19
18 (1 eq) 14 (1 eq) MeO2C Ph
22 *PPA2 H
R = 2,4,6-iPr3C6H2
H Ar1
H Ar1 N
N *PPA2
*PPA2
Ar2
Ar2 b) Representative Examples
R 2N Rh
O R 2N Rh Ar1 Bn2N Ph Bn2N Ph
O N R 2N NH NH
OMe
OMe Ar2 CO2Me Ph p-BrC6H4
Ph 20
Ph MeO2C Ph MeO2C Ph
21
Ph
19a, 51% (dr = 95:5) 19b, 71% (dr = 95:5)
ee = 97% ee = 99%

S. Jia, D. Xing, D. Zhang and W. Hu, Angew. Chem. Int. Ed. Engl., 2014, 53, 13098–13101. 9
3) Trapping With Michael Acceptors:
The Synthesis of γ-Hydroxyketone Derivatives
H2O (1.5 eq) CO2Me
O (S)-tBu-BOX-Zn(OTf)2 Ph OH
Ph CO2Me (30 mol %) O
1 N
+ Ar Rh2(OAc)4 (2 mol %)
Ar1 N
N2 N TsOH (40 mol %)
23 (1 eq) Me 24 N
1 (2.5 eq) CH2Cl2, -8 °C Me

BOX b) Representative Examples
24b: X = Br
Rh Zn(OTf)2 CO2Me CO2Me (78%, dr = 97:3, ee = 96%)
Ar O Ph Ph
OH OH 24c: X = NO2
MeO2C + N O O
(86%, dr = 95:5, ee = 90%)
O Ar1 N N
H H 24d: X = OMe
23 - Zn N (60%, dr = 92:8, ee = 99%)
25 Me N
X
N
HOTs Me Me
24a, 96%,
dr = 94:6, ee = 96%
CO2Me MeO
O O Ph OH CO2Me CO2Me
O OH OH
O Cl O
N N N
Ph N Ph N
tBu tBu N
Me N N
26 (S)-tBu-BOX 24e, 75% 24f, 80% Me 24g, 72% Me
dr = 86:14, ee = 95% dr = 99:1, ee = 93% dr = 99:1, ee = 85%

X.-Y. Guan, L.-P. Yang and W. Hu, Angew. Chem. Int. Ed., 2010, 49, 2190–2192. 10
3) Trapping With Michael Acceptors:
The Synthesis of Chiral Indolines
a) O R1
R2 Rh2(OAc)4 O
R 1 (1 mol %) Ar H O
Sc(OTf)3/L2-PrPr3 R1 R O
R2
NH2 (1:1.2, 10 mol %) O N R
27 (1 eq) H
THF, 5Å MS, 25 °C Sc H N Ar
N2 +
R *L Cl H
30
Ar 29 – favored TS
O 28 (2 eq)

b) Representative Examples

Ph O Ph
N N
O O O
O O O O O
O O
iPr H H iPr Me Me Et
iPr iPr N Ph N Ph F3C N Ph
H H H
30a, 88% 30b, 93% 30c, 79%
iPr 31 – L2-PrPr3 iPr ee = 90% ee = 88% ee = 99%

J. Yang, C. Ke, D. Zhang, X. Liu and X. Feng, Org. Lett., 2018, 20, 4536–4539. 11
3) Trapping With Michael Acceptors:
The Synthesis of γ-Sulfur Substituted Ketones
a) CO2Me
Rh2(OAc)4 (2 mol %) CO2Me CO2Me
Ar1 Ar1
Ar1 N2 Sc(OTf)3 (10 mol %) O O
1 (1.5 eq) R 1S + R 1S
R1 SH O
4Å MS, CH2Cl2, rt R2 R3 R2 R3
32 (1.5 eq) + 34 – syn 34 – anti
R2 R3
33 (1 eq) 34a: Ar1 = Ph; R2 = Ph; R3 = Ph: 74%, dr = 80:20
34b: Ar1 = Ph; R2 = m-ClC6H4; R3 = Me: 68%, dr = 93:7
34c: Ar1 = Ph; R2 = Me; R3 = Me: 45%, dr > 95:5
b) Proposed Mechanism
CO2Me
Ar1
O
R 1S
R2 R3 RhLn
R3 34 SR1
Ar1 CO2Me
O 38 Ar1 CO2Me
R1HS N2 1
R2 37 – 1,2-H shift
Ar1 CO2Me undesired
Ar1 CO2Me
Sc(III)
O Rh 35

R2 R3 R1 SH
32
Rh
Sc(III)
R1HS Rh R1HS O
O
Ar1 CO2Me
R2 R3 Ar1 OMe
33 36
G. Xiao, C. Ma, X. Wu, D. Xing and W. Hu, J. Org. Chem., 2018, 83, 4786–4791. 12
4) Trapping with Gold Activated Alkynes:
The Synthesis of Tetrahydrofurans and γ-Butyrolactones
O b) Representative Examples
Rh2(esp)2 R R1
R3 O O
CH2Cl2, O Ph O Ph
MeO O MeO O
O 10 min
b) Limitation of synergistic Rh/Ag/Au catalysis
R 3 O/H,H
R1 O O O
Ph MeOC Rh2(esp)2
N2 O Me H
N2 PPh3AuOTf
1 PPh3AuOTf + EtO2C O
65, 83% 66, 77% CO2Et HO CH2Cl2, 4Å MS
+ R = COR', 2h dr > 98:2 MeOC Me 72
instantly
R3 R = Ph, no reaction
70 71
64%,, dr > 98:2
O O O
H
O Ph Ph via
O O O
2 /H,H Rh2(esp)2/ R R1 Ph O Ph PPh3AuOTf
O Rh2(esp)2
PPh3AuOTf
O O MeOC N2
CH2Cl2, Ph Me
3 CO2Et
Instantly O/H, R 67, 87% 68, 82%
H 4
dr > 98:2
dr > 98:2

A. C. Hunter*, S. C. Schlitzer and I. Sharma, Chem. Eur. J., 2016, 22, 16062–16065. 13
4) Trapping with Gold Activated Alkynes:
The Synthesis of Various Spiroethers
O O O O
N2 HO Rh2(esp)2 or Rh2(TFA)4 (1 mol%) O
PPh3AuSbF6 (10 mol%) N Rh2(esp)2
X + X O N2 PPh3AuSbF6 N N
CH2Cl2, 4Å MS N
R R O CH2Cl2, 4Å MS O O
+ reflux D O
Ph
b) Representative Examples HO
O O O 79, 62% Ph
DMB DMB Ph O [95% D]
O O DMB O Ph
N N N O O
D
O
O O O O
77, 63% 78, 33% 79, 65% N2
79, 42% Ph
dr > 20:1 dr = 2:1 dr > 20:1
O O
Ph Ph Ph Rh2(TFA)4
O N PPh3AuSbF6
O O O
N O Cl MeO N
+ O
O O O O Ph CH2Cl2, 4Å MS D
N N N HO 0 ºC
N
O 79, 63%
dr > 98:2
79, 62% 79, 79%a 79, 60%a 79, 63%a [95% D]
dr > 98:2 dr > 98:2 dr > 98:2
D

A. C. Hunter*, S. C. Schlitzer, J. C. Stevens, B. Almutwalli and I. Sharma, J. Org. Chem., 2018, 83, 2744–2752 14
4) Trapping with Gold Activated Alkynes:
The Synthesis of Various Spiropyrollidines
Ph
O O Ar
HN Rh2(esp)2 (1 mol%)
PPh3AuSbF6 (10 mol%) N
N2 +
CH2Cl2, rt, 4Å MS
80 81 82

b) Representative Examples

O Ph O Ph O Ph O Ph
O Ph
N N O N N N
Ph N
MeO O
O N
O O O

83, 60% 85, 62% 86, 41% 87, 52%
85, 62%

c) Deuterium Labeling Experiments

Ph H
N2 Rh2(esp)2 (1 mol%)
HN N Ph
O PPh3AuSbF6 (10 mol%) D 90, 62%
+ O [67% D]
CH2Cl2, rt, 4Å MS
D 89
88

A. C. Hunter*, B. Almutwalli, A. I. Bain and I. Sharma, Tetrahedron, 2018, 74, 5451–5457. 15
4) Trapping with Gold Activated Alkynes:
Proposed Mechanism

O O
X Rh2(esp)2
N2 80
93 – N2

O

Au(I) Rh(II)
Rh(II)
O 88 X
X
H H H
O X
– Rh(II)
90
X – Au(I) 91 Au(I) Au(I)
92 Au(I)

PPh3AuSbF6 H
X
89

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5) Trapping with Pd-π-allyl Complexes :
The Synthesis of Furan-Scaffolds

O Rh2(tBuCO2)4 (1.0 mol%)
O
O [PdCl(allyl)]2 (2.0 mol%) R
CO2Et b) Representative Examples
Xantphos (2.2 mol%)
+
N2 R O Ph toluene, rt OMe Br Cl
O O CO2Et
94 (1.1 eq) 95 (1 eq) MeO
Me 98
R
Pd(0)
O O O O Br O
[Pd(II)] – Pd(0) O O O O O
Rh(II) – PhCO2Me CO2Et CO2Et CO2Et CO2Et CO2Et
O O
97 O
Ph 99, 89% 99, 98% 99, 69% 99, 96% 98, 96%
CO2Et
O O R O O O Br
CO2Et CO2Et O
Me [Pd(II)] Br
O [Rh] O O CO2Et O CO2Et O CO2Et
Me Me O O
96 – Rh(II) 99, 80% 99, 40% 99, 87%
Ph

Z.-S. Chen, X.-Y. Huang, L.-H. Chen, J.-M. Gao and K. Ji, ACS Catal., 2017, 7, 7902–7907. 17
5) Trapping with Pd-π-allyl Complexes :
The Synthesis α-Quaternary Chiral β-Lactams
R4
a) Rh2[(s)-tert-PTTL]4 (1 mol%)
O O Pd(dba)2 (2 mol%)
R3 rac-BINAP (2 mol%) O
R1 N BocO R4 O
N2 104 n-Hexane, 25 °C, 24 h
H R2 R1
N
103 R2 R3
Pd(0) 108
tBuO dr up to 99:1
Pd
-CO2 ee up to 98%
RhLn R4
O O O 107
R3 R1 O
R1 N
-N2 [Rh] R2 N Diastereoselective
H R 2
R3 allylic alkylation
105 Enantioselective 106
C-H Insertion b) Representative Examples

R1 = 2-CH3 (68%, dr = 91:9, 74% ee)
O R2
O R1 = 3-CH3 (89%, dr = 88:12, 87% ee)
R1 = 2-CF3 (54%, dr = 95:5, 61% ee)
Ph R1 = 4-OMe (84%, dr = 88:12, 91% ee) O
N O
R1 = 4-F (97%, dr = 87:13, 97% ee)
Ph
R2 = 2-CH3 (42%, dr = 86:14, 82% ee)a N
R1 R2 = 4-CH3 (67%, dr = 88:12, 89% ee)a Ph Bn
arac-BINAP ligand was replaced with Xantphos

L.-Z. Huang, Z. Xuan, H. J. Jeon, Z.-T. Du, J. H. Kim and S. Lee, ACS Catal., 2018, 8, 7340–7345. 18
5) Trapping with Pd-π-allyl Complexes :
The Synthesis of Amino Vinyl Carboxylates/Ethers
N Rh2(tBuCO2)4 (1.5 mol%)
N NSO2R' Pd2(dba)3 (2.0 mol%) X
X +
Xantphos (2.2 mol%) NSO2R
109 (1 eq) R2 110 (1.2 eq) R2
toluene, 50 °C 111
O O O OR1
-N2 X= or
X= or
R1 O R 1O O R1 O (-CO2)

c) Proposed Mechanism

N RhLn
N NSO2R'

R2
110
Pd
– N2 X
X NSO2R' NSO2R
[Rh] R2
111
NSO2R' [Rh] R2 118
R2 Pd (0) X= R1CO2
116 X= R1O (after -CO2)

Pd (0)
XPd X
117 109

Z.-S. Chen, L.-Z. Huang, H. J. Jeon, Z. Xuan and S. Lee, ACS Catal., 2016, 6, 4914–4919. 19
5) Trapping with Pd-π-allyl Complexes :
The Synthesis of Amino Vinyl Carboxylates/Ethers

b) Representative Examples
O O O O
Ph O O O Me O
NTs NTs NTs
Ph MeO Ph NTs
O2N Ph Ph
XX, 86% XX, 76% XX, 44% XX, 70%

O O O O

Ph O Ph O Ph O Ph O
NTs NTs NTs NTs

Me Me MeO NC
XX, 0% XX, 89% XX, 81% XX, 0%
(84% at 70 ºC) (33% at 70 ºC)

Ph OtBu Ph OEt

N Ph N Ph
Ts Ts
XX, 70% XX, 46%

Z.-S. Chen, L.-Z. Huang, H. J. Jeon, Z. Xuan and S. Lee, ACS Catal., 2016, 6, 4914–4919. 20
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