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Phosphine Catalysis: Generation of Phosphonium Enolates Justin Roberts Organic Supergroup January 25, 2006 •Lu, X.; Zhang, C.; Xu, Z. Acc. Chem. Res. 2001, 34, 535-544. •Methot, J. L.; Roush, W. R. Adv. Synth. Catal. 2004, 346, 1035-1050.
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Transcript of Phosphine Catalysis - Home | Princeton Universityorggroup/supergroup_pdf/jproberts... · Phosphine...
Phosphine Catalysis: Generation of Phosphonium Enolates
Justin RobertsOrganic Supergroup
January 25, 2006
•Lu, X.; Zhang, C.; Xu, Z. Acc. Chem. Res. 2001, 34, 535-544.•Methot, J. L.; Roush, W. R. Adv. Synth. Catal. 2004, 346, 1035-1050.
Why Phosphine?• Leaving group potential
– pKa Et3PH+ = 8.7 better LGEt3NH+ = 10.7
• Nucleophilicity
– K1/K2 > 500– ↑ with e- donating alkyl groups on phosphine
• Phosphonium stabilizes adjacent carbanion
Et2PhP I
I
+
+Et2PhN
Et2PhP+
Et2PhN+
K1
K2
I-
I-
•Davies, W. C.; Lewis, W. P. G. J. Chem. Soc. 1934, 1599.
Outline
R3P+
O-
X
R'
R' X
O
R"
OH
X
O
R'
EWGX
O
YX
OR"
R'
Y
X OR"
R'
R'X
O
Nu
R'X
Nu
Oor
NuR'
O
X
R'
Internal Redox
R3P+
O-
X
R'
R' X
O
R"
OH
X
O
R'
EWGX
O
YX
OR"
R'
Y
X OR"
R'
R'X
O
Nu
R'X
Nu
Oor
NuR'
O
X
R'
•Ketones, esters, amides•AcOH promotes reaction•More nucleophilic phosphines produced considerable amounts of oligamers.
•R3N or (RO)3P = NR•E,E-diene selective
R
O
R'R' R
O10 - 40 % PPh3
80 - 140 °C
•O
O O
OPPh3, PhCH3
60 °C, 2 h
69 - 88 %
90 %
•Trost, B. M.; Kazmaier, V. J. Am. Chem. Soc. 1992, 114, 7933-7935.•Guo, C.; Lu, X. J. Chem. Soc., Chem. Commun. 1993, 1921-1923.
OMe
OOMe
O O
OMePh3P
H
Ph3P
Ph3P
H O
OMe
O
OMe
O
OMe
O
OMe
Ph3P
Ph3P
H
Ph3P
O
OMe
Ph3P
A
AH
A AH AH
A
Ph3P, AH
•Rychnovsky, S. P.; Kin, J. J. Org. Chem. 1994, 59, 2659-2660.
n-C6H13O
O
n-C6H13 O
O
PPh3, PhOH55 °C, 12 h
70 %
PPh3, PhOH55 °C, 14 h
n-Bu
On-Bu
O21 %
•E & Z enynes transfer selectively to E,E,E-trienes•Ynoates transfer to dienes @ rt with PhOH
R1OH
O
R2R1 R2
O
Ph3P, rtPhH, 8 h
R1 R2 R1 R2
PPh3
OH O
PPh3OO
•R2
OR1
Ph3P=O
R1
EtnPrnPrEt
R2
OEtOEtnBu
n-C5H11
85 %86 %83 %86 %
•Guo, C.; Lu, X. J. Chem. Soc., Chem. Commun.1993, 394-395.
Morita-Baylis-Hillman Reaction
R3P+
O-
X
R'
R' X
O
R"
OH
X
O
R'
EWGX
O
YX
OR"
R'
Y
X OR"
R'
R'X
O
Nu
R'X
Nu
Oor
NuR'
O
X
R'
CNR H
O
CNCN
Ph3P
CN
Ph3PR CN
CN
Ph3P
R
O
R
OHCN
cat. PCy3120 °C, 2 h R
OHCN+ <23 %
RCHO
RCHO
PCy3
•Morita, K.; Suzuki, Z.; Hirose, H. Bull. Chem. Soc. Jpn. 1968, 41, 2815.•Basavaiah, D.; Rao, A. J.; Batyanarayana, T. Chem. Rev. 2003, 103, 811-891.•Stephen Goble “The Morita-Baylis-Hillman Reaction” Organic Supergroup Meeting,November 19, 2003.
Entry R Lewis Base % yield % ee
1 PhCH2CH2 A 88 90 2 Cy B 71 96 3 iPr B 82 95 4 Ph A 40 67 5 PhCHCH B 39 81
•Li, W.; Zhang, Z.; Ziao, D.; Zhang, X. J. Org. Chem. 2000, 65, 3489-3496.
•McDougal, N. T.; Schaus, S. E. J. Am. Chem. Soc. 2003, 123, 12094-12095.
N N
O
O
OH
O
O
H
O
+ 10 % catalystDCM, rt, 9 h
catalyst = PHO
HO
R H
O O
R
OH O+ 10 % Lewis Base
PEt3, 48 hTHF, -10 °C
OHOH
X
X
A: X =
B: X =
83 %, 17 % ee (+)
O
TolS
R
O
R
HNS
TolOO
10 % PhPMe2PhMe+
RPhCH2CH2 71 % 84 % deBu 52 % 82 % dem-FC6H4 76 % 76 % dep-BrC6H4 83 % 86 % dem,p-Cl2C6H3 80 % 80 % de
Ph3P
NH
R
STol
OOSi face
•Shi, M.; Xu, Y. Tetrahedron Asym. 2002, 13, 1195-1200.
Rauhut-Currier Reaction
R3P+
O-
X
R'
R' X
O
R"
OH
X
O
R'
EWGX
O
YX
OR"
R'
Y
X OR"
R'
R'X
O
Nu
R'X
Nu
Oor
NuR'
O
X
R'
•Rauhut, M.; Currier, H. U. S. Patent 3074999 1963
OEt
O
CN
cat. PBu3
EtO OEt
OO
PPh3, tBuOHMeCN, 45 °C NC CN
•Reaction let to polymerization without proton donor toterminate process
•Baizer, M. M.; Anderson, J. D. J. Org. Chem. 1965, 30, 1357-1360.
O O OPPh3, 118 °C
15 - 30% conv.
PPh3 or P(p-tolyl)3tBuOH or Et3SiOH
160 - 175 °C
CN NC CN
Ar3PCN
CNAr3P
CN
CNAr3P
CN H+ transfer
78 % in Et3SiOH60 % in tBuOH
•McClure, J. D. U. S. Patent 3,225,083 1965.•McClure, J. D. J. Org. Chem. 1970, 35, 3045-3048.
•Increased rate with polar solvent•PBu3addition is indiscriminate: 5-member ring is trapped by
cyclization6-member ring cyclizationbecomes rate determining
Ph
O
n
10 % PBu3
O
Ph
O Ph
O
O+
nn
n = 1
n = 2
1 : 1 79 %
7 : 1 77 %
OEtO OEt
O
O
O
EtO
O
+10 % PBu387 %
>95 : 5
O
O
•Wang, L.; Luis, A. L.; Agapiou, K.; Jang, H.; Krische, M. J. Am. Chem. Soc. 2002,124, 2402-2403.
O
O2N
O
O
O
O
O2N
OMe
MeO
NO2
Ph
Ph
O
PhO
10 % PBu375 %
10 % PBu385 %
10 % PBu381 %
+
>95
5
:
Ph
O
Ph
O Ph
O
Ph
O
+
>95 : 5
Ph
O
O
O
Ph
O
+
>95 : 5
O
OMe
O
O
OEt
OO
OBn
OBn OBn
O O
OBn BnO
OBn
OBn OBn
BnO
O O
20 % PBu371 %
MeOCOBn
OBnOBn
PBu3
EtO2C
+
>95 : 5
TBSO
TBSO CHO
CHO TBSO
TBSO
CHO
CHO
30 % PBu3MeCN, 14 h
90 %10:1 dr
•Frank, S. A.; Mergott, D. J.; Roush, W. R. J. Am. Chem. Soc. 2002, 124, 2404-2405.
PBu3
R1
O
Bu3P
R2O
R1
OR2O
O
R1
O R2
O R2O
R1
H
Bu3P
n
n
n
n
•With acetone-d6, not deuterium incorporation was observed
OR
R'
O
OR
R'
O25 - 100 % PMe3
R R'
Me OMe
Me Me
H Me
H OMe
83 %
46 %
45 %
47 %(67 % in MeCN)
23 % aldol
20 % aldol
O O
O OHMe3PH
O
O
Me3P O O
OO
Me3P
HH
PMe3 H+ transfer
•Presumably PMe3 is slow to eliminate allowing for proton transfer
HSEt
OSEt
O
O
O
O
OH
O
O
O
20 % PBu3tBuOH, 135 °C
81 %
Ricciocarpin
3 steps
•Agapiou, K.; Krische, M. J. Org. Lett. 2003, 5, 1737-1740.
•Thioenolates work well with MBH reactions
•Keck, G. E.; Welch, D. S. Org. Lett. 2002, 4, 3667-3690.
[3+2]
R3P+
O-
X
R'
R' X
O
R"
OH
X
O
R'
EWGX
O
YX
OR"
R'
Y
X OR"
R'
R'X
O
Nu
R'X
Nu
Oor
NuR'
O
X
R'
CO2Et• CO2Me+ 10 % PPh3, rtPhH, rt81 % CO2Et CO2Et
CO2Me
CO2Me
+
80 : 20
CO2Et•CO2Et
EtO2C+
CO2Et CO2Et
CO2Et CO2Et
CO2EtCO2Et +10 % PPh3
CO2Et
trans
cis
trans
cis
+ 10 % PBu3
67 %
46 %
88 %
91 %
1
0
:
:
0
1
1
1
0
0
:
:
" " "
•Ketones & nitriles
•Zhang, C.; Lu, X. J. Org. Chem. 1995, 60, 2906-2908.
PR3CO2Et•CO2Et CO2Et
CO2Me
CO2Me
+
CO2Et CO2Et
CO2Me
CO2Me
+
Ph3P Ph3P
CO2Et CO2Et
CO2Me
CO2Me
+
Ph3P Ph3P
Ph3PCO2Et
Ph3PCO2Et
Ph3PCO2Et
Ph3PCO2Et
+
CO2Me CO2Me
CO2Et• + CO2R
PPh
Pri
iPrCatalyst =
CO2Et CO2Et
CO2R
CO2R10 % CatalystPhH, rt +
R %yield %ee A:B
A B
Et 87 79 (R) 96:4iBu 92 88 (R) 100:0iBu 88 93 (R) 100:0tBu 75 88 (R) 95:5
0 °C
•Zhu, G.; Chem, Z.; Jiang, Q.; Xiao, D.; Cao, P.; Zhang, X. J. Am. Chem. Soc.1997,119, 3836-3837.
CO2Et•
R
NTs+ 10 % PPh3
PhHN
CO2Et
Ts R
RH
OMeNO2
98 %98 %88 %
Ph3PCO2Et
NTs
Ph3P CO2Et Ph3P CO2EtPh3P
CO2Et
NR
NTs
RTs
RR
NTs
•Ts protection is necessary•One regioisomer
•Xu, Z.; Lu, X. Tetrahedron Lett. 1997, 38, 3461-3464.•Xu, Z.; Lu, X. J. Org. Chem. 1998, 63, 5031-5041.
CO2Et•R NPhTs+
N
CO2Et
TsN
CO2Et
Ts
+20 % PBu3PhH, rt1.5 - 8 h
Me 89 % 91 : 9Et 99 % 95 : 5iPr 99 % 100 : 0tBu 99 % 100 : 0Ph 99 % 100 : 0
R
PhRPhR
•Aryl aldimines only•PBu3 necessary for initial 1,4-addition
•Zhu, X.; Henry, C. E.; Kwon, O. Tetrahedron 2005, 61, 6276-6282.
•Zhu, S.; Henry, C. E.; Wang, J.; Dudding, T.; Kwon, O. Org. Lett. 2005, 7, 1387-1390.
CO2iPr• R H
O
R
O O
R
CO2iPr
Ph3PCO2
iPr
CO2iPr
Ph3P Ph3PCO2
iPr
R O
Ph3PCO2
iPr
ORO
R
R
R
Ph3PCO2
iPr
+
R H
O
R H
O
4-Py 99 %4-CF3-C6H4 99 %3-CF3-C6H4 90 %2-CF3-C6H4 65 %3-MeO-C6H4 47 % n-Pr 0 %
R
20 % PMe3, CHCl3, rt
•Wang, J.; Ng, s.; Krishe, M. J. J. Am. Chem. Soc. 2003, 125, 3682-3683.•Wang, J.; Krische, M. J. Angew. Chem., Int. Ed. 2003, 42, 5855-5857.
MeO
OO R O
MeO H
H
RO
10 % PBu3, 110 °CEtOAc (0.1 M)
40 - 48 h
RPhSEt
2-furylc-Pr
76 %78 %74 %86 %
MeO2CO
10 % PBu3, 110 °CEtOAc, 88 %
MeO2C H
H
HH
H
O
6 steps
Hirsutene
1 isomer
•Pyne, S. G.; Schafer, K.; Skelton, B. W.; White, A. H. Chem. Commun. 1997, 2267-2268.
CO2Et• BzN O
O
Ph BzN O
O
Ph
BzN O
O
Ph
EtO2C
CO2Et
+ 10 % PPh3 + + dimer
49% 17 % 27 %
CO2Et•
CO2EtPPh3
BzN O
O
Ph
+ 10 % PPh3
BzN O
O
Ph
CO2Et
H 38 % singe isomer
O
N
O
BzH
Ph
[4+2]
R3P+
O-
X
R'
R' X
O
R"
OH
X
O
R'
EWGX
O
YX
OR"
R'
Y
X OR"
R'
R'X
O
Nu
R'X
Nu
Oor
NuR'
O
X
R'
Free hydroxyl or pyrrolyl groups were disastrousAliphatic imines, if stable to reaction conditions, gave 85 %with NaCO3
R NTs CO2Et•+
N
CO2Et
TsR20% PBu3
DCM, rt
R = aryl, alkyl
NArTs CO2Et•+
Ar'
N
CO2Et
TsAr20% PBu3
DCM, rtAr' quant.
>9:1 dr
>85 %
•Zhu, X. F.; Lan, P.; Kwon, O. J. Am. Chem. Soc. 2003, 125, 4716-4717.
CO2Et•
CD3
PBu3
CO2Et+PBu3 +PBu3
CO2Et
R NTs
N ND ND
+PBu3
CO2Et
TsD
TsR
CO2Et+PBu3
+PBu3
CO2Et
RTs
N
N
DCO2Et
R DD
Ts
CO2Et+PBu3
RTs
R
D
- -
--
-
-
H+ transfer
H+ transfer
•Tran, Y. S.; Kwon, O. Org. Lett. 2005, 7, 4289-4291.
NN
Ts CO2Et•+N
N CO2EtTs
CO2Et
CO2Et30% PBu3
DCM, rt
73 %3:1 dr
NNMe
OH
H
H
NNMe
OH
H
H
NNMe
O
H
HO
O
H
H
H
H
(+)-Macroline
(-)-Alstonerine
9 steps
31 %(26 %, 12 steps)
•When BOC protected indole was used, 84 %, 1.1:1 dr
CO2Et•+
CO2Et
NPhTs
5 % (R)-1DCM, rt
NTs
CO2Et
CO2EtPh
P
(R)-1
93 %, 91:1 dr98 % ee
•>5 % catalyst needed without 2nd ester group•Various aromatic aldimines tolerated•Yields 75-99 %, >96 % ee, >9:1 cis:trans
•Wurz, R. P.; Fu, G. C. J. Am. Chem. Soc. 2005, 127, 12234-12235.
Umpolung
R3P+
O-
X
R'
R' X
O
R"
OH
X
O
R'
EWGX
O
YX
OR"
R'
Y
X OR"
R'
R'X
O
Nu
R'X
Nu
Oor
NuR'
O
X
R'
EWG
E2
E1+ cat. PPh3
HOAc/NaOAcPhCH3, 80-110 °C
E1 EWGE2
EWG = ester, ketone, amideE1, E2 = ketone, ester, nitrile, SO2R
Phosphine acts as a nucleophilic triggerSuitable pronucleophiles: pKa < 16
Less EWG reacts better with less acidic nucleophile
•Trost, B. M.; Li, C.-J. J. Am. Chem. Soc. 1994, 116, 3167-3168.
Ph3P
PPh3
EWG
PPh3
EWG
Nu-H
EWG
EWGPPh3
Nu
EWGPPh3
Nu
EWGPPh3
Nu
EWG Nu
H+-transfer H+-transfer
OH CO2Me OH OCO2Me
CO2Me+
PPh3, HOAc, PhCH3, 110 °CPPh3, HOAc, DMSO, 110 °Cdppp, HOAc, PhCH3, 85 °C
47 %91 %3 %
53 %9 %97 %
OH
CO2MeH CO2Me
OH
H
O CO2Menn n
+
Hdppp, HOAcPhCH3, 85 °C
n = 1 trans cis
n = 2 trans cis
84 %-
--
-69 %
75 %55 %
•Trost, B. M.; Li, C.-J. J. Am. Chem. Soc. 1994, 116, 10819-10820.
PPh2Ph2P
•
OMeO
PPh2Ph2POH
PPh2O
OMe
Ph2POH
CO2MeOH
PPh2O
OMeOH
Ph2P
OPPh2
OMe
OPh2PH
OPPh2
OMe
OPh2P
OOMe
O
H
H+
CO2Et•
E1 E2 E1 CO2Et
PhO CO2Et
E2
56 - 87 %
98 %PhOH
PhH, rt, 5 % PPh3
CO2Et•5 % PPh3, PhH, rt
BnO CO2Et BnOCO2Et
BnOH
BnOH, 20 % AcOH
20 %
90 %
35 %
-
•α-substituents require more nucleophilic phosphine andlonger reaction times
•γ-substituents give redox products
•Protonation of initial enolate requires higher acidity•Zhang, C.; Lu, X. Synlett 1995, 645-646.
PPh3
CO2Et•CO2Me
CO2Me
Ph3P
CO2MePh3PPh3PCO2Me
BnO CO2Me BnO CO2Me BnOCO2Me
Ph3PCO2Me
Ph3PCO2Me
PPh3
BnOH
BnO
BnOH
Path A Path B
BnO BnO
PPh3 PPh3
90° rotation
BnO BnO
CO2Et + HN
O
O
CO2EtPh +
+ H2NTs
10 % Ph3P, PhMe, 105 °C50 % HOAc/NaOAc, 18 h
Nu
CO2Et
Nu
CO2EtPh
PhNu
CO2Et
CO2Et
"
"
"
"
95 %
82 %
82 %
+ H2NTs HOAc/NaOAcPhMe, 105 °C
PPh3 (92 %)
dppp (45 %)
CO2Et CO2Et+
HNTs
1 : 7.3
1 : 0
•Phthalimide requires phenol as cocatalyst•Trost, B. M.; Dake, G. R. J. Am. Chem. Soc. 1997, 119, 7595-7596.
•Highly stereoselective•PM3 calculations:
O
O
Ph
O
RR
H
n n-120 % PBu3
12 h, THF, rtPh
O
n = 2
3
4
63 %
73 %
0 %
O
H
H
O
PMe3O
H
H
O
PMe3vs.
-54.05 kcal/mol-93.44 kcal/mol
2.44 Å
1.45 Å
•Kuroda, H.; Tomita, I.; Endo, T. Org. Lett. 2003, 5, 129-131.
Michael Reaction
R3P+
O-
X
R'
R' X
O
R"
OH
X
O
R'
EWGX
O
YX
OR"
R'
Y
X OR"
R'
R'X
O
Nu
R'X
Nu
Oor
NuR'
O
X
R'
EWGNO2 NO2 EWG+ PR3, rt
0.2-0.4 M THF
CO2Et
O
CN
CN
CN
Entry Olefin Cat. (mol %) Time (h) % yield
1 PBu3 (0.5) 1.5 82
2 “ PMePh2 (1) 1.5 79
3 “ PMe2Ph (5) 20 80
4 “ PPh3 (0.5) 160 36
5 “ “ 24 78
6 PBu3 (1) 1 70
7 PBu3 (0.5) 1 21
8 PBu3 (1) 16 75
9 PBu3 (10) 20 33
NO2in
•White, D. A.; Baizer, M. M. Tetrahedron Lett. 1973, 14, 3597-3600.
OZ
Z ZO
Z20 - 95 %MeCN or THF
3-20 % PR3, rt+
Z = ester, ketone
•PPh3, PBu3, PCy3, dppf•Discovered while studying Ru catalyzed Michael reaction
-phosphine ligand thought to dissociate
•Gómez-Bengoa, E.; Cuerva, J. M.; Mateo, C.; Echavarren, N. M. J. Am. Chem. Soc. 1996, 118, 8553-8565.
CO2MeMeO2CO
MeO2CO
CO2Me
MeO2C
MeO2C
O
CO2MeMeO2C
OO
O
O
O
+
+
+
MeCN, rt
3 % PBu3
3 % PCy3
3 % dppf
0.1 h, 95 %
0.1 h, 82 %
8 h, 84 %
95 %
55 %
MeCN, rt3 %, PPh3, 12 h
THF, rt20 % PCy3, 48 h
"
"
R NOH R
OSO2Ph
YSO2Ph+
Y
MeCN (2.0 M)20 % PPh3, 65°C, 2 h
N
Entry R Y % yield
1 H 90
2 H 96
3 py H 88
4 iBu H 89
5 Cy H 88
6 H 90
7 Me 84
8 Et Me 84
O2N
MsO
MsO
•Bhuniya, D.; Mohan, S.; Narayanan, S. Synthesis, 2003, 7, 1018-1024.
R NOH R N
OEWG
YEWG+
Y
MeCN (2.0 M)20 % PPh3, 65°C, 2 h
A: R = m-NO2C6H4, Y = HB: R = Ph, Y = Me
Entry Oxime EWG % yield
1 A CO2Et 80
2 B “ 50 (75)a
3 A CN 80
4 B “ 62 (75)a
5 A SO2Ph 95
6 B “ 87
7 A COMe 87
8 B “ 85a Reaction in parenthesis run with 3 eq. acceptor for 16 h
@ rt.
O O
OMe
5 % catalystMeOH, 45 °C
M-BPE =
PP
2 2
Entry Catalyst Time (h) % conv.
1 PMe3 6 95
2 PBu3 6 95
3 Me-BPE 4 93
4 Quinuclidene 48 54a
5 DABCO 16 0a
6 O=PMe3 20 0a
a 10 % catalyst.
•Stewart, I. C.; Bergman, R. G.; Toste, F. D. J. Am. Chem. Soc. 2003, 125, 8696-8697.
Entry EWG R1 ROH Time (h) % yield
1 COEt Me H2O 20 77
2 “ “ MeOH 24 85
3 COMe H MeOH 1 56
4 “ “ Me2CHOH 1 83a
5 “ “ PhOH 16 59a
6 CO2Me Me MeOH 36 71
7 CN H MeOH 4 79a MeCN as solvent.
R1
EWG
R1 OR
EWG5 % PMe3ROH (1 M)
Ph
O5 % PMe3
MeOH NR
O O
Ph3P
O
O
RO
O
RO
O
Ph3P
O
Ph3P
Ph3P
ROH
O5 % PMe3
CD3OD
5 % PMe3CD3OD
O
no exchange
O
D DD Dquant.
RO
Conclusions
• Simple & readily available
• Various reactions stemming from phosphonium enolate
• Efficient reactivity
• Lesson: Always run the control experiment
