SnAP Reagents for the One-­‐Step Synthesis of Medium-­‐Ring Saturated N-­‐Heterocycles from Aldehydes Cam-­‐Van T. Vo, Michael Luescher, and Jeffrey W. Bode Nature Chemistry. doi:10.1038/nchem.1878 Current Lit 3-­‐15-­‐14 James Johnson 1 HO
James Johnson @ Wipf Group Medium-­‐ring saturated N-­‐
heterocycles OH
HO
OH
NH
Cl
N
H
Cl
Iminocyclitols
PNMT inhibitor
OH
O
N
N
H
O
N
OH
N
O
dovyalicin B
N
N
H
(+)-Quebrachamine
Otonocine
O
H
N
N
(+)-Rhazinilam
Saturated N-­‐heterocycles as drugs J. Am. Chem. Soc. 1996, 118, 7647-­‐ 7652; J. Med. Chem. 1996, 39, 3539-­‐3546. Org. Le<. 2003, 5, 2793-­‐2796; J. Am. Chem. Soc. 1998, 120, 3613-­‐3622 Nat. Chem. 2012, 4, 130–133 2 Ar-X, M
PdLn
N
Li
Boc
n
X
N
N
R
Ar
ArMgBr (2 eq)
Fe(acac)3 (5 mol %)
t-BuOMe, 50 °C
15-30 min
X = i, Br
n
N
Bn
t-BuCOMe (5 eq)
150 °C, 4-19 h
Nakamura
Ar
ArB(OR)2
Ru3(CO)12 (3.3 mol %)
N
Dieter
CuCN LiCl Pd(PPh3)4, (chiral Li)
Campos ZnCl2, Pd(OAc)2, P(t-Bu)3 - HBF4 (chiral Li)
Knochel ZnCl2, Pd2dba3, RuPhos
Ar
N
Ar-CN, NaOAc
Ir(ppy)3 (1 mol %)
DMA
23 °C, 12 h
Sames
N
N
N
R
James Johnson @ Wipf Group α-­‐Arylation of cyclic amines N
R
Ar
MacMillan
3 JACS 2001, 123, 5132 – 5133; JACS 2006, 128, 3538–3539; JACS 2011, 133, 4774 – 4777; JACS 2010, 132, 5568 – 5569; JACS 2006, 128, 14220 – 14221; Science 2011, 334, 1114 – 1117. Bu3Sn
H
R
O
Bu3Sn
MS 4Å
S
S
Cu(OTf)2
2,6-lutidine
H2N
CH2Cl2
2 h, r.t
R
N
4:1 CH2Cl2:HPIF
12 h, r.t.
X
MS 4Å
Bu3Sn
X
Cu(OTf)2
2,6-lutidine
S
R
James Johnson @ Wipf Group Previous work 23 examples
40-77%
N
H
R = aryl, alkyl
Bu3Sn
H
Me
R
O
CH2Cl2
2 h, r.t
H2N
Me
R
N
4:1 CH2Cl2:HPIF
12 h, r.t.
X
R
R = aryl, alkyl
Boc
N
Boc
N
Boc
N
Boc
N
N
H
75%
N
H
64%
N
H
58%
N
H
O
75%
O
O
N
H
79%
N
N
H
N
<10%
O
NH
O
O
N
H
85%
N
H
O
84%
S
OEt
Boc
N
Boc
N
N
H
79%
dr > 10:1
N
H
O
57%
dr > 10:1
N
H
79% O
dr > 10:1
N
H
X= O, NBoc
Boc
N
OEt
O
O
OEt
30 examples
Me 5-94%
OEt
N
H
O
51%
dr > 5:1
N
H
63%
dr = 5:1
O
OEt
N
H
80%
dr > 10:1
N
4 Vo, C.V.T., MikuUs, G., Bode, J.W., Angew. Chem. Int. Ed. 2013, 52, 1705 –1708 Luescher, M.U., Vo, C.V.T, Bode, J.W., Org. LeZ. 2014, 16, 1236-­‐1239 Bu3Sn
X
H
R
N
H
F3C
MS 4Å
CH2Cl2, 2 h, r.t
O
O
X= O, NBoc
O
N
H
HO
Ph
F3C
75%
d.r. = 10:1
O
O
N
H
N
H
NC
O
O
N
H
N
H
78%
BocN
N
H
43%
Ph
EtO
Ph
MeO2C
N
Ph
H
67%
d.r. > 10:1
HN
Boc
N
N
H
N
H
N
H
F3C
F3C
86%
66%
Boc
N
O
N
H
EtO
N
H
62%
Boc
N
O
EtO
N
H
66%
O
Boc
N
Boc
N
N
H
N
H
N
H
83%
78%
N
N
N
Boc
N
O
Nature Chemistry. doi:10.1038/nchem.1878 R
Boc
N
65%
N
X
O
41%
O
O
N
O
71%
d.r. = 9:1
O
4:1 CH2Cl2:HPIF
12 h, r.t.
O
74%
d.r. = 9:1
52%
Cu(OTf)2 (1 eq)
2,6-lutidine (1 eq)
X
55%
O
Br
R
H2N
86%
EtO
Bu3Sn
N
H
59%
MeO
N
H
72%
James Johnson @ Wipf Group Seven-­‐membered rings O
N
H
83%
5 Bu3Sn
H
R
O
O
MS 4Å
n
Bu3Sn
CH2Cl2, 2 h, r.t
H2N
R
m
X = O, NBoc
n = 0, 1; m = 1, 3
O
O
N
n
m
Cu(OTf)2
2,6-lutidine
4:1 CH2Cl2:HPIF
12 h, r.t.
O
O
Cl
R
O
n
HN
m
Boc
N
O
HN
F3C
N
H
MeO2C
46%
Boc
N
HN
O
HN
F
45%
38%
20%
O
O
Boc
N
N
H
39%
N
H
79%
James Johnson @ Wipf Group Eight and Nine-­‐membered rings O
N
H
34%
F3C
N
H
52%
EtO
O
N
O
N
H
F3C
F3C
68%
72%
EtO
O
HN
N
H
42%
N
O
6 O
HN
41%
N
H
MeO
51%
Br
O
HN
29%
N
N
N
H
EtO
O
O
O
O
HN
35%
22%
Bu3Sn
X
R
N
X
HFIP
R
Cu(II)
Cu(I)
X
X
R
CuII
N
H
James Johnson @ Wipf Group Mechanism R
N
H
N
H
X = S, O, NBoc
7 Bu3Sn
N
N
Cu(OTf)2
S
S
2,6-lutidine
4:1 CH2Cl2:HPIF
12 h, r.t.
N
N
H
Bu3Sn
S
N
F3C
N
TEMPO
Cu(OTf)2
2,6-lutidine
4:1 CH2Cl2:HPIF
12 h, r.t.
O
S
N
F3C
S
N
N
trace
Bu3Sn
James Johnson @ Wipf Group Mechanistic Studies CuLn
N
NaCNBH3
AcOH, MeOH
O
S
N
H
F3C
8 •  SnAP provides an alternaUve method for the synthesis of medium-­‐sized N-­‐heterocycles. •  Uses mild reacUon condiUons. •  SnAP reagents air and moisture stable. •  Stoichiometric in Cu and Sn •  Future James Johnson @ Wipf Group Conclusions •  Intermolecular variant Bu3Sn
Boc
N
O
9 N
R
R
R
N
NH
N
5-exo
N-attack
6-endo
C-attack
favored by
3.4 kcal/mol
James Johnson @ Wipf Group R
5-exo
6-endo
1:50
10 HSnBu3
H2N
1) LDA, THF
-78 °C - 0 °C
2) (CH2O)n, THF
rt, 4h
73%
HSnBu3
K2CO3
NIS. PPh3
Bu3Sn
OH
Bu3Sn
THF
rt, 12h
93%
1) LDA, THF
-78 °C - 0 °C
2) (CH2O)n, THF
rt, 4h
3) MsCl, THF
-78°C - rt, THF
89%
SH
I
Bu3Sn
EtOH:H2O
70 °C, 12h
98%
S
H2N
James Johnson @ Wipf Group Synthesis of SnAP Reagents: NaI
Bu3Sn
Cl
acetone
rt, 16h
98%
Bu3Sn
I
11 Angew. Chem. Int. Ed. 2013, 52, 1705 –1708 HO
n
OH
NaH, Bu3SnCH2I
THF/DMF,
15h, 50 °C
n = 1: 94 %
n = 2: 97 %
Bu3Sn
1) MsCl, Et3N,
Et2O, 2 h, r.t.
n OH
O
2) K+ Phthalimide
DMF, 3 h, 100 °C
Bu3Sn
EtOH, 0.25 h
reflux
n = 1: quant.
n = 2: quant
OH
O
O
n N
O
O
1)Bu3SnCH2I
K2CO3, Acetone
reflux, 12h
O
SnBu3
NH2
2) NaH, Bu3SnCH2I
DMF, 3h, r.t. 76 %
NH2NH2 • H2O
EtOH, 0.3h
reflux
n
OH
O
SnBu3
n
NH2
n = 1: 99 %
n = 3: quant.
1) LAH, THF
16h, 0 °C, 79%
2) NaH, Bu3SnCH2I
DMF, 16h, r.t. 85 %
3) MsCl, Et3N,
Et2O, 2 h, r.t.
4) K+ Phthalimide
DMF, 3 h, 100 °C
90 % (2 steps)
SnBu3
O
1) LAH, THF
3h, 65 °C, 92%
NH2
2) Phthalimide,
DIAD, PPh3,
THF, 16h, r.t.
1) n = 1: 69 %; n = 3: 89 %.
2) n = 1: 66 %; n = 3: 95 %
OH
OH
OH
n NH2
n
OH
O
Bu3Sn
n = 1: 88 % (2 steps)
n = 2: 64 % (2 steps)
O
NH2NH2 • H2O
O
James Johnson @ Wipf Group Synthesis of SnAP Reagents O
O
N
SnBu3
O
NH2NH2 • H2O
EtOH, 0.3h
reflux
quant.
O
NH2
SnBu3
12 NH2
OH
Cl
+H
3N
Cl
1) Boc2O, THF, 24h
2) TIPSCl, im,
CH2Cl2, 15 h, r.t
90 % (2 steps)
H
N
3) NaH, Bu3SnCH2I
DMF, 1h, 0 °C 91 %
4) TBAF, THF,
1 h, r.t. 96%
1) Boc2O, Et3N
CH2Cl2, 18 h,
r.t. 97%
2) NaH, Bu3SnCH2I
DMF, 3h, r.t. 76 %
SnBu3
OH
O
Bu3Sn
N
N
Boc
O
1) Phthalimide,
DIAD, PPh3,
THF, 24h, r.t.
Boc
N
SnBu3
2) NH2NH2 • H2O
EtOH, 0.3 h, reflux
quant.
NH2
1) K+ Phthalimide
DMF, 0.75 h,
100 °C , 81%
2) NH2NH2 • H2O
EtOH, 0.3 h, reflux
95%
Bu3Sn
N
Boc
James Johnson @ Wipf Group Synthesis of SnAP reagents NH2
13 Br
NH3
Br
1) Boc2O, CH2Cl2
18h, rt, quant.
2) K+ Phthalimide
DMF, 24 h, r.t 91%
3) NaH, Bu3SnCH2I
DMF, 5h, 0 °C 71%
4) NH2NH2, EtOH
reflux 30 min 95%
NH2
OH
OH
OH
Boc
N
SnBu3
OH
NH2
NH2
1) Boc2O, CH2Cl2
18h, rt, 89%
Boc
N
SnBu3
2) TIPSCl, Im, CH2Cl2
18h, r.t. 87%
3) NaH, Bu3SnCH2I
DMF, 5h, r.t., 86%
OTIPS
1) NaH, Bu3SnCH2I
THF/DMSO, 15h,
55 °C, 71%
2) MsCl, Et3N, Et2O
1h, r.t.
3) K+ Phthalimide
DMF, 3 h, 100 °C
82% (2 steps)
O
N
O
SnBu3
O
1) TrCl, Et3N
CH2Cl2 16h, r.t. 92%
O
2) NaH, Bu3SnCH2I
DMF, 5h, r.t. 98%
3) AcOH, CH2Cl2,
TFE, 4h, r.t. 90%
Boc
N
SnBu3
1) TBAF, THF,
1h 0 °C
2) Phthalimide,
DIAD, PPh3,
THF, 18h, r.t.
80% (2 steps)
3) NH2NH2, EtOH
reflux 45 min, 95%
NH2NH2
EtOH, 0.3h
reflux
quant.
NH2
SnBu3
James Johnson @ Wipf Group SnAP for Substituted Piperazines/ Morpholines NH2
O
SnBu3
NH2
14 15 James Johnson @ Wipf Group