Synthetic possibilities Chem 315 Beauchamp 1 z:\files\classes\315\315 Handouts\synthesis target molecules W 2012.doc Propose reasonable syntheses for the following target molecules (TM-#). You can use the given starting materials and any typical organic reagents studied in our course (or even outside our course if you know them). Reaction Conditions (in our course) Alkane reagents Br 2 h O 2 1 2 3 4 5 6 7 8 SN/E reagents (react with methyl, primary, secondary, tertiary, allylic, benzylic RX patterns via SN2/E2 or SN1/E1)) O R O Na O R Na O H Na S R Na 1. N 3 Na 2. LiAlH 4 3. WK 1. 2. NaOH N O O Na O K S H Na 2 3 4 5 6 7 8 1 hydroxide alkoxides carboxylates enolates hydrogen sulf ur anion phthalimide anion azide alkyl sulf ur anion Alkene reagents (H 2 SO 4 /H 2 O) HBr 1. Hg(OAc) 2 /H 2 O 2. NaBH 4 1. Hg(OAc) 2 ROH 2. NaBH 4 1. H 3 B 2. H 2 O 2 / HO (D 2 SO 4 /D 2 O) DBr 1. Hg(OAc) 2 /H 2 O 2. NaBD 4 2 3 4 5 6 7 8 1
Transcript
Synthetic possibilities Chem 315 Beauchamp 1
z:\files\classes\315\315 Handouts\synthesis target molecules W 2012.doc
Propose reasonable syntheses for the following target molecules (TM-#). You can use the given starting materials and any typical organic reagents studied in our course (or even outside our course if you know them).
Reaction Conditions (in our course) Alkane reagents
Br2
hO2
1 2 3 4 5 6 7 8
SN/E reagents (react with methyl, primary, secondary, tertiary, allylic, benzylic RX patterns via SN2/E2 or SN1/E1))
Aldehyde reagents – follow all reactions with a workup step
2 3 4 5 6 7 812 eqs ROH
TsOH (-H2O)
make ketals& acetals
HOOH
TsOH (-H2O)
make ketals& acetals
Na
CN
make cyanohydrinsslow addition of acid
Na
CC
R
terminal acetylides organometallic
R
Li
(MgBr)or
S
S
Lidithiane anion
Ph3PCH2
Wittig reactionmakes alkenes
O
Li
enolates
aldol reactions
CrO3 / H2OJones
oxidize tocarboxylic acids
H2O2 ormCPBA
oxidize tocarboxylic acids
RNH2
pH 5(-H2O)
make imines make enamines Clemmenson reaction Wolff-Kishner rxn make enolates react enolates
NH
pH 5(-H2O)
H2NNH2
RO NaZn / HCl
NLi
LDA, -78oC
1. LDA, -78oC
2. RX
9 10 11 12 13 14 15 16
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Ketone reagents – follow all reactions with a workup step
Acid reagents
Kochi reactionmakes R-Br
Pb(OAc)4 / LiBr(-CO2)
9 10 11 12 13 14 15 16
H3PO4
Friedel-Craftsacylation
Acid chloride reagents
Amides
Anhydrides
Amines
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Ethers
Nitriles
Alpha-beta unsaturated carbonyl compounds
1,3-dicarbonyl compounds
Aromatic chemistry
Template
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34
Br
Br
Br
Br
Br
BrBr
Br
Br
Br
Br
Br Br Br
Br
Br
BrBr Br
Br
Br Br
Br BrBr
Br
BrBr Br
BrBr
Br
Br Br
BrBr
BrBr
Br
BrH3C Br Br
Br
Representative RX patterns from C1 - C7: 1C (1), 2C (1), 3C (2), 4C (4), 5C (8), 6C (17) and 7C (39) examples, not counting stereoisomers such as enantiomersand diastereomers - in our course, many of these can be made from: a. f ree radical substitution, b. alcohols or c. alkenes. You have to know the limitations (our rules)of SN / E chemistry (strong vs weak), (more basic vs less basic), C substitution patterns, C substitution patterns, etc.
Br
Br
Br
Br
Br
Br
BrBr
Br
Br Br Br1 2 3 4 5 6 7 89 10
11 12 13 14 15 16Br
Br
Br
BrBr
Br
Br
BrBr
Br Br
BrBr Br
Br
BrBr
17 18
19 20 21 22 23 24 25
26 27 28 29 30 31 32 33
2C 3C 4C 5C
5C 6C
6C
6C 6C
6C
1C
35 36 37 38
39 40 41 42 43
44 45 46 47 48
49 50 51 52 53
54 55 56 57 58 59
60 61 62 63 64 65
66 67 68 69 70 71 72
7C 7C
7C7C
7C 7C
7C7C
7C 7C
7C7C
7C 7C
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34
OH
OH
OH
OH
OH
OHOH
OH
OH
OH
OH
OHOH
OH
OH
OH
OHOH OH
OH
OH OH
HO OHOH
OH
OHOH
OHOH
OH
OH
OH OH
OHOH
OHOH
OH
OHH3C OH OH
OH
Representative ROH patterns from C1 - C7: 1C (1), 2C (1), 3C (2), 4C (4), 5C (8), 6C (17) and 7C (39) examples, not counting stereoisomers such as enantiomersand diastereomers - many of these can be made from: a. RX compounds, b. alkenes c. carbonyl compounds or d. epoxides
OH
OH
OH
OH
OH
OH
OHOH
OH
OH OH OH1 2 3 4 5 6 7 89 10
11 12 13 14 15 16OH
OH
OH
OHOH
OH
OH
OHOH
OH OH
OHOH OH
OH
OHOH
17 18
19 20 21 22 23 24 25
26 27 28 29 30 31 32 33
2C 3C 4C 5C
5C 6C
6C
6C 6C
6C
1C
35 36 37 38
39 40 41 42 43
44 45 46 47 48
49 50 51 52 53
54 55 56 57 58 59
60 61 62 63 64 65
66 67 68 69 70 71 72
7C 7C
7C7C
7C 7C
7C7C
7C 7C
7C7C
7C 7C
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Representative alkene patterns from - many of these can be made from: a. RX compounds, b. ROH c. Wittig reaction (C=O compounds) or d. alkynes
1 2 3 4 5 6 7 8 9
10 11 12 13 14 15 16 17
18 19 20 21 22 23 24
25 26 27 28 29 30 31 32
33 34 35 36 37 38 39
40 41
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H
O
O
O
OO
H
1 2 3 4 5 6 7 8
9 10 11 13 14
15 16
O
O O
O
O O
OO
O
O
O
O
O
O
17 18 19 20 21 22
23 24 25 26 27 28
O
H H H
O
O
H
O
O
H
O
H
O
HH
12O
HH H
H
HH
H
H
Representative aldehyde and ketone patterns from - many of these can be made from a. alcohols or, b. alkynes or c. nitriles or d. esters or e. acid chlorides orf . carboxylic acids or g. alkenes or h. other reactions we don't know. The aldehydes can be made into caroboxylic acids, alcohols and alkenes, imines, enamines,enolates, enol ethers, acetals and more. Acids can be made into esters, acid chlorides (many possibilities), alcohols, ketones and more. Ketones can be made intoalcohols, alkenes, esters, enol ethers, enolates, enamines, imines and more.
O
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OO
O
2 3 4 5 6
78 9 10 11
13 14 15 16
OO
OOO
OO
O17
O
H O O
O
O
O
O
O
O
O
OO
12
O
OO
OO
O
OO
O
H
Representative acid patterns from - many of these can be made from a. 1o ROH, b. alkenes (O3) c.
H
O
OH H H
HH
2
HH H
HH
H HH H
H O
O
H
O
O
H O
O
H O
O
H
18 19 20 21
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O O
N
2 3 4 5 6
7 8 9 10 11
13 14 15 16
O O
O O
O
O
O17
O
H N N
O
N
O
N
O
N
O
N N
12
O
N N
N NN
N N
N
R
Representative amide patterns (1o, 2o, 3o, R = C or H from - can be made from a. acid chloride +,ammonia or a 1o or 2o amine b. nitriles can make 1o amides
R
O
NR R R R R
1
H H H R R
R R R R
RN
O
R
N
O
RN
O
R N
O
R
18 19 20 21
R
R R R R R R
ROR
R R RR
R RR R
R
RRR
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34
NH2
NH2
NH2
NH2
NH2
NH2NH2
NH2
NH2
NH2
NH2
NH2 NH2NH2
NH2
NH2
NH2NH2
NH2
NH2
NH2NH2
H2N NH2
NH2
NH2
NH2
NH2NH2
NH2
NH2
NH2
NH2NH2
NH2NH2
NH2 NH2
NH2
NHH3C
NHNH
HN
Representative R3N patterns (R = C or H) from C1 - C7 skeletons: 1C (1), 2C (1), 3C (2), 4C (4), 5C (8), 6C (17) and 7C (39) examples, not counting stereoisomers such as enantiomersand diastereomers - many of these can be made from: a. RX compounds and 1. phthalimidate b. 2. NaOH or 1. NaN3 2. LiAlH4 3. workup or c. nitrile + LiAlH4 2. workup d 1. aldehydesor ketones + NH3, RNH2 or R2NH (-H2O) 2. NaH3BCN 3. workup
HN
NH
NH
HN
HN
NH
HN HN
NH
NHNH HN
1 2 34 5 6 7 8 9
10
11 12 13 14 15 16 HN
HN
HN
HNHN HN
NH
NH HN
NH2 NH2
NH2NH2 NH2
NH2
NH2
NH2
17 18
19 20 21 22 23 24 25
26 27 28 29 30 31 32 33
35 36 37 38
39 40 41 42 43
44 45 46 47 48
49 50 51 52 53
54 55 56 57 58 59
60 61 62 63 64 65
66 67 68 69 70 71 72
R
R
R
R
R RR R R
R
R
R
R R R
R
R
R
R
R R R
R
R R
Ritter rxn
Ritter rxn
Ritter rxn
Ritter rxn
Ritter rxn Ritter rxn
Ritter rxn
Ritterrxn
Ritter rxn
problemfor us
problemfor us
problemfor us
problemfor us
problemfor us
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The following are useful transformations using the given alkane starting points. Reagents are not given over the arrows, but possibilities are suggested below each list by number.
BrH3C
CH4
1
2
OHH3C
OH3C
OH3CR
O
R SHH3C
NH2H3C
CH3C
N
CH3C
CR
3 45 6 7 8
1
Br2h
2 O
R O
Na
OR
Na
OH
Na
SH
Na
1.
2. NaOH
N
O
O
1. N3 Na
Na2. LiAlH43. WK
Na
CN
Na
CC
R3 4 5 6 7 86 9 10 11
LiH3C
(MgBr)H3C
CH3
9 10 11
Limetal
Mgmetal
C6H6 + AlBr3(aromatic chem)
OH
H3C
O
H H
O
H OH
BrH3C
OH3C R
OH3C
O
R
1 2 3 4 5
HBr orPBr3 orSOBr2 ora. TsCl/pyb. NaBr
CrO3/py(PCC)
CrO3/H2O(Jones)
1
1. NaH2. RX (SN2)
RX(SN1)
4
O
R Cl
2 3 54
O
R OH
TsOH (-H2O)Fischer ester syn
5
O
H H
OHH3C
1. NaBH42. WK
1 1
1. LiAlH42. WK
H H
R
1 2
O
H OH
N
H H
R
3 4
R OH C OHOH
NR
765
2 3
CrO3/H2O(Jones)
R P(Ph)3
Wittig rxn
4
RNH2
pH = 5(-H2O)imines
LiR
(MgBr)R
1. 1.
2. WK 2. WK Na
CN
Na
CC
R5 5 6 7
Assume all reactions finish with a workup step.
O
H OH OR
O
H
OHH3C
1. LiAlH42. WK
1. NaOH2. RX (SN2)
only
Cl
O
H
1C = unstable
O
H R
1 2 43
1 2 3
SOCl2(but no good for 1C acid)
4
LiR
1. 2 eqs.
2. WK
Assume all reactions finish with a workup step.
1
2 3 4 5 6 7 8
1
Br2h
2 3
9 10 11
Br OH O O SH NH2 C Li (MgBr)R
O
R
N
H2O1. O
O2. NaOH
2
ROH(SN1)
(SN1)
O
O
4
NaNa
5
SH
Na
1.
2. NaOH
N
O
O
1. N3 Na
Na2. LiAlH43. WK
6 6
Na
CN
7 8 9
Limetal
Mgmetal
10
O
K
11
C6H6 + AlBr3(aromatic chem)
1 2 3 4 5
Na
6
OH Br O OR
O
O
OTs
1HBr orPBr3 orSOBr2 ora. TsCl/pyb. NaBr
2
CrO3/py(PCC)
CrO3/H2O(Jones)
2 3
1. NaH2. RX
(=Me,1oRX, SN2)
3
RX
(=2o,3oRX, SN1)
4
O
R O
5
H2SO4 / (E1 rxns)
6
Ts-Clpyridine
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1
NR
2 3
R OHC OH OH
NR6 754
O OH
R
O
O
1. NaBH42. WK
1 1
1. LiAlH42. WK
2
R P(Ph)3
Wittig rxn
3
mCPBA
4
RNH2
pH = 5(-H2O)imines
5
LiR
(MgBr)R
51. 1.
2. WK 2. WK
6
Na
CN
7
Na
CC
R
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Reaction Worksheet Possible Approaches
1
1. Na+ R2N2.
3. WKBr
Br
Br
1. Na+ R2N2. WK
Br21. K+ R3CO2. WK
Br havailable
3 equivalents
Br2
2
1. Na+ R2N2.
3. WK
H3C Br
Br
Br
1. Na+ R2N2. WK
Br21. K+ R3CO2. WK
Br havailable
Br2
3 equivalents
3 45
2
Na / NH3
2
Pd / H2 quinoline (Lindlar's cat.)
Pd / H2 quinoline (Lindlar's cat.)
1
26
Pd / H2
1 34
5
Use any of these.
6
LiAlH4
BrBr13 14
Use either of these.
D
D
7RS / SR
Pd / D2
4
D
D7RR / SS
Pd / D2
3
Br2
hBrNaOH
8 available15
1
O
H
9
1. R2BH2. H2O2 / HO
O
H
9
CrO3 pyridine
OH11
O
H
9
1. O3 , -78oC2. CH3SCH3
has to be made
21
O
10
H3O+ / H2O (Hg+2 cat.)
Either of these. O
10
CrO3 / pyridine or CrO3 / H2O
OH
12
O
10
1. O3 , -78oC2. CH3SCH3
has to be made
OH
12
OH
11
1. H3B2. H2O2 / HO
5OH
11Br
13
H3O+ / H2O
Any of these.
Na+ HO
1. Hg(OAc)2 / H2O2. NaBH4
or
OH
12
1.LiAlH4 2. WK
Any of these.
OO
O OH
12
1.CH3CO22. NaOH
Br
14
OH
12
Br
14
H2O
(or NaBH4)
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Br
13
1. H3B2. Br2 / CH3O
5Br
13
HBr orPBr3
OH11
Br
13
1. Ts-Cl, py.2. NaBr
OH11
Br
14
Any of these.
5
3
4
HBrBr
14
HBr
OH
12
Br
14
Br2
12h
1. H3B2. Br2 / CH3O
Br
816(15 is prepared in 8)
O
17
Br
14
CH3OH
O
17
OH
12
1. NaH 2. CH3Br
The other ethers are prepared in a similar way using SN1 and SN2 reactions.
18,19,20,21 1. H3B2. H2O2 / HO
OH
8for 21
1. H3B2. Br2 / CH3O
Br
8for 21
OH
for 21Br
HBrNaOH OH
for 21
Br
NH2
22
1.
2. NaOHBr
13
N
O
O
NH2
23
Br
14
1.
2. NaOH
N
O
O
Br13
31
1. NaNR22.
(from 1)OH
24
O
OH
CrO3 / H2O
11
H
O
or9
OH24
O
O
25,26,27,28,29,30 (similar)
O
R
1. NaOH 2. RBr
Br13
C
N32
NaCN Br
14
C
33
N
NaCN C N
34
NaCN BrBr2
h
available
Br
35
1. NaNR22.
136 is similar
36
1. NaNR22.
136 is similar
Br
1. H3B2. Br2 / CH3O
1.K+ (CH3)3O2. NaOH
Br
Br2
havailable
OO
O
5
mCPBA or1. Br2 / H2O2. NaOH
3839
37 3 4
mCPBA or1. Br2 / H2O2. NaOH
mCPBA or1. Br2 / H2O2. NaOH
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O37
NH2
40
1.
2. NaOH3. WK
N
O
O
OH
O 1. NaCN37
41 OH
1. NaNR22.
(from 1)
3. WKO37
C
OH
N
2. WK42
H3O+ / H2O
O37OH
43
or H2O / HO
OH
O37
44
OH 1. NaH2.
3. WKCH3HOO
CH3
O3745
O
CH3HO
OH
TsOH
Br2
5Br
46
Br
Br2 / H2O
5OH
47
Br
Br2 / CH3OH
5O
48
Br
39
NH2
48
OH
O
S
R
and RS O
O
4938
OH
49
OH
OH
OH
H3O+ / H2O or H2O / HO
H3O+ / H2O or H2O / HO
39
1.
2. NaOH
N
O
O
O
O
4938
OH
49
OH
OH
OH
H3O+ / H2O or H2O / HO
H3O+ / H2O or H2O / HO
39
3938
OH
50
NH2
50
OH
OO
NH2R
and SS
SR
R
and RS
1.
2. NaOH
N
O
O
1.
2. NaOH
N
O
O
O38 339
CH3OH2+ / CH3OH
or CH3OH / CH3O
O
51
O
OH
CH3OH2+ / CH3OH
or CH3OH / CH3O51
O
OH
Br2
Br
Br
52
4
Br2
Br
52 3
OH
Br
53 453
Br2 / H2O
Br2 / H2O
Br
Br
OH
1. NaNR22.
O 3956
OH 3. WK
3
O
Br
54454
Br2 / CH3OH
Br
O Br2 / CH3OH
1. NaNR22.
38
563. WK
O
O39
55
C
OH
N
2. WK
1. NaCN
55 2. WK
1. NaCN
O
38
57 and 58 are similar with
O
mCPBA or1. Br2 / H2O2. NaOH
OH
C
N
OH
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1. NaNR22.
9
59 3. WK 2. WK
1. NaCN
OH
O
H
60C
N
OHO
H9(from 1)
1. NaNR22.
613. WK
1
O
OH
2. WK
1. NaCN
62
OH
O
1. NaNR22.
10
633. WK
O
1
HOO
2. WK
1. NaCNHO C
N
64 1. Li+ R2N = (LDA)2.
O
3. WK
O
65
O37
1. Li+ R2N = (LDA)2.
O
3. WK
O
H
OOH
66
9
OH
O1. Li+ R2N = (LDA)2.
O
3. WK
Br
O
67
1. Li+ R2N = (LDA)2.
O
3. WK
10O
68
HO
1. Li+ R2N = (LDA)2. O
3. WK
O
69
1. Li+ R2N = (LDA)2. O
3. WK
O
70
BrBr
1314
1. Li+ R2N = (LDA)2.
O
3. WK
O
71
1. Li+ R2N = (LDA)2.
O
3. WK
O
72
BrBr
14
Br
Br
1.LiAlD4 2. WK
(or NaBD4) 1373
D
D74
1.LiAlD4 2. WK
(or NaBD4) O 38
1.LiAlD4 2. WK
(or NaBD4)
HO
D
R
R
(also SS)
75
76 O37
1.LiAlD4 2. WK
(or NaBD4)
D
OHO 39
1.LiAlD4 2. WK
(or NaBD4)
75OH
D
S
R
(also RS)
O
H9
1.LiAlD4 2. WK
(or NaBD4)
OH
D
77
1.LiAlD4 2. WK
(or NaBD4) O10HO D
781. Li+ R2N = (LDA)2. WK
OOH
O
O
79 80 OH
1. Li+ R2N = (LDA)2. WK
or
O
OH
81
1. Li+ R2N = (LDA)2. WK
1. O3 , -78oC2. CH3SCH3
H
O
H H
O
82 1. O3 , -78oC2. NaBH4OH
83
CH3HO
1. O3 , -78oC2. H2O2 / HO
OH
O
H OH
O84
Br
Br
Br2
85
Synthetic possibilities Chem 315 Beauchamp 19
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