Heterocyclic Chemistry by D. R.

Mal 2013

Q1. Nomenclature: Suggest an IUPAC names for each of the following structures.

O O

A B

Key1.

A: (1R, 6S)-7-Oxabicyclo[4.1.0]hept-2-ene

B: (1aR, 7aS)-1,6,7,7a-tetrahydronaphtho[1,2-b]oxirene

Q2. Name the following.

H
N
O O Ph
N
N N N Ph
N B O
Ph Ph H

A: a PyBox ligand B C: CBS oxazaborolidine

N N O N N
H
N N O
N
O

D: caffeine E: nicotine F

Key 2.

A. PyBox ligand: 2,6-Bis(4S-phenyl-4,5-dihydrooxazol-2-yl)pyridine

1
B: Octadecahydrodibenzo[c,h][1,5]naphthyridine

C: 1,3a-Dimethyl-3,3-diphenyltetrahydropyrrolo[1,2-c][1,3,2]oxazaborole

D: 1,3,7-Trimethyl-3,7-dihydropurine-2,6-dione

E: 3-(1-Methylpyrrolidin-2-yl)-pyridine

F: 2,4,4-Trimethyl-4,5-dihydrooxazole

Q3. Suggest the structure of [A] and [B]

PhB(OH)2,
K2CO3, DMF,
NaNO2, HCl Ac2O heat
NH CO2H
[A (C9H8N2O2)] [B]

Key 3. Sydnones; [2013 SNT Ynag Y] Oxidative coupling.

N O
N O O
O N
N

O
O

[A] [B]

Q4. Electrophilic substitution: Propose mechanistically the structures of A and B in the

following scheme.

i) I2, aq. NaHCO3

[A] [B]
HN O ii) CH3I, Ag2O heat
CO2Me
(C7H9NO4)

2
Key 4. [2009 OL 1233 Padwa A]

MeI, Ag2O
H2O
HN I O CHO O OH O OMe
O NH N N
CO2Me CO2Me CO2Me CO2Me

H H

Diels-Alder O N OMe
reaction CO2Me

Q5. Complete the following sequence of reactions with necessary reagents and
conditions.

OTBMS OH OTBMS OTBMS

OHC a O b O c

e O
O d O
O O O

Key5. [1988 JOC 860 Kanematsu K]

a. 2-Bromo-1-methylfuran, n-BuLi; b.(Ph0)3P+MeI-, HMPA, 25 C; c. i) Bu4NF, THF; ii)

n-BuLi, propargyl bromide, benzene/DMSO; d. t-BuOK, t-BuOH, 83 C; e. 5% CSA,
CH3CN/H20 (2:l); f. Ag2C03, celite, benzene, reflux

Q6. Suggest a reasonable mechanism for the following.

3
 CO2Et
Ph O O Mn(OAc)2 (10%), AcOH
OEt Ph N
N3 methanol, 40 oC
H

Key 6.

EtO
EtO
O
Ph O
O O N2
Ph O
N O
OEt N
N
Mn(OAc)3 N

CO2Et
CO2Et

Ph N
Ph N OH H

Q7. Apply the concept of combination Barton-Zard and van Leusen pyrrole synthesis for
the synthesis of
STol

N Ts
H

Key 7.

STol
STol
DBU, TosMIC
THF Ts
O2N OAc N
H

STol STol
STol STol H
O2N O2N

O2N N Ts
N Ts N Ts
N Ts H

4
Q8. Propose an appropriate synthetic route for the following conversion.

O OHC O

Key 8.

i) n-BuLi OHC O
O O DMF, POCl3

ii) allyl bromide Vilsmeier reaction

Q9. Complete the following route with appropriate reagents and substrates.

S
Br Br
S S Cl S
O
S

Key 9. [1994 THN 8699]

NBS SO2Cl2 Mg
MgBr
Br Br
Cl S
S S Cl S

A
Mg

DMF
MgBr CHO
S S

MnO2 S NaOMe S
A +B S

S DMF S
HO S O Cl O OMe
Cl

5
Q10. Suggest the sequence with reagents for the transformation below.

O O
one-pot CHO

Si Si I

Key 10. [1995 ACIE 2683 Curran DP]

i) t-BuLi
ii)
O O O OLi
N CHO
N Li
N
iii) N
Si Si Si Li

O
I2 CHO

Si I

Q11. Predict the products of the following sequence.

O
TBSO
N CO2Me
O O n-BuLi OTBS
[A] [B}

Key 11. [2005 science 395 Myers]

O N O
N O O
O n-BuLi N
O TBSO
C4-lithiation Li TBSO O OBn
N
N
[B]
[A]

6
Q12. Devise a synthetic route for the following

NO2

N H2N N

Key 12.

N
N NH2
N
conc. HNO3 NO2
NO2
ZnCl2, tert-BuOK
DMSO, rt H2N N
N N

Q13. Suggest the products of the following reactions.

a.
N
HCONH2, H+, tBuOOH, FeSO4
S 0 oC

b.
CH3CHO, aq. H+, tBuOOH, FeSO4
N

Ph N

Key 13.

N N
HCONH2, H+, tBuOOH, FeSO4
CONH2
S 0 oC S

O
Mechanism: tBuOOH BuO + CH3
O NH2

O
CH3CHO, aq. H+, tBuOOH, FeSO4
N N

Ph N Ph N

7
Q14. Complete the sequence given below.

OTHP OTHP
O OBn
TMS
Br Br
a b

N N N

Key 14. [1994 THN13575]

a. LDA, THPOCH2CO2Et

b. i) NaBH4; ii) NaH, BnBr iii) Trimethylsilylacetylene, (Ph3P)4Pd, Et3N.

Q15. Suggest three electrophilic reagents which would promote quaternization of

pyridine nitrogen like MeI does with pyridine.

MeI
N I
N

Key 15.

1. NO2BF4 2. MeCOCl or PhCOCl 3. SO3

Q16. Provide a mechanism for the 1st step of the following sequence.

EtO2C
CO2Et
N
EtO2C CO2Et NHAc
HO-
NHAc Na Tryptophan
N N
H Toluene, heat H

Key 16.

EtO2C
N CO2Et
Et2NH EtO2C CO2Et NHAc

NHAc Na
N
N N
H
H

8
Q17. Suggest a synthetic for

CO2Et
N
O

Key 17.

ethyl formate,
dry HCl, N CO2Et KOEt
NH.HCl
isopropanol H2N CO2Et
O O
NaCN

CO2Et
N CO2Et
N
O
O O

Q18. Work out the mechanism of the following transformation.

CO2Et
CO2H
PCl5 N
N Cl
OEt O
Ph
Ph O

Key 18.

CO2Et
CO2H
PCl5 N
N Cl
OEt O
Ph
Ph O
PCl5

CO2Et
CO2Et
CO2H N
N OH
N OH O
OEt O Ph
Ph
Ph O

9
Q19. Work out the mechanism of the following transformation.

R O R N
NH2CHO

R N
R OH H

Key 19.

H R H
OH R N N
R
R O NHCHO CHO CHO
NH2CHO
R OH R O
R OH
R OH H

R H H H
N R R N
CHO N
NH2CHO CHO OH
R NHCHO NHCHO N
OH R R
CH
O
H2O
R H
N

R N

Q20. Propose a mechanism for the following transformation.

O2, H2O, eosin

CHO O
O HO O

Key 20. [1985 THN 2057 Gollnick K]

1
O2 OH
CHO CHO HCO2H
O O O O
O
O O O O HO O
H
O2, H2O, Rose Begal = 1O2

10
Q21. Suggest a route for the following elaboration.

O
O

N
H N
CO2H H

Key 21. [2013 OL Shibasaki M]

OH OTBS
O TBSCl, imidazole, DMF
Eaton reagent
N N O N O
H 1:10 P2O5:MsOH
CO2H H H

OTBS (Ph3P)2PdCl2 O
Tf2O, 2,6-lutidine aq NaHCO3, ethanol, toluene
CH2Cl2
N OTf N
O H
B
O

Q22. Suggest a synthesis of the following.

Ph
NC

H2N N Ph

Key 22. [2007 JMC 828]

NC Ph Ph
Ph
NC NH4OAc NC
N
product
N Ph N HN Ph
O Ph
Micahel addition

11
Q23. Predict the product of the reaction below.

N N rt, water/org. solvents

N N N N

Key23. [2008 JACS 13518 Fox JM]

N N
H H
N
N N
N HN N
N N N N N
N

Q24. Predict the product of the reaction below.

OBu-t Et3N, CH2Cl2

O
10 oC to rt
p-Tol N PhO
N Cl

Key 24.

O O
OBu-t
Et3N, CH2Cl2 PhO
OBu-t O
10 oC to rt
p-Tol N PhO N
N Cl Tol-p
O N

HCl
O
OPh
OBu-t
p-Tol N
N
O

12
Q25. Suggest a mechanism

N Toluene, heat
O
N

Key 25. 2010 JACS 13203 Danheiser RL

N Ene reaction
O
H O
O N
H N N
H

Q26. Suggest a good synthetic route for the following.

O
O
O
N

Key 26. [2013 EJOC Mal D]

MeO2C ether MeO2C

O rt K2CO3, CH3I
+ + Conc. NH3 MeO2C
MeO2C
O Cl N
H

O
MeO2C HO2C CH3COCl,
KOH, MeOH, O
water ClCH2CH2Cl
MeO2C HO2C O
reflux
N N N

13
Q27. Explain the formation of the intermediates of the scheme below and suggest a
suitable mechanism for each of the steps.

TfO step 1
O TfO step 3 OTf
OTES
NaHMDS O TfOH, - 78 oC
Triethylsilyl OH
O chloride (TESCl) Py, MeOH
O H
HO O
O
O step 2
PhMe, reflux
TIPSO TIPSO
TIPSO

Key 27. [2011 JACS 12451 Funk RL on cortistatin]

OTf
OTf
O TESO
NaHMDS
Triethylsilylchloride Toluene, reflux
O O O O
kinetic silyation
O retro-Diel-Alder
O reaction

TIPSO TIPSO

OTf
OTf
H
TESO O
TfOH O H
H+ HO
O [4 + 3] cycloaddition
O

TIPSO

TIPSO

Q28. Propose a mechanism for the following furan ring construction.

14
 OTBS OTBS
AgNO3
O O

Key 28.

OTBS OTBS
OTBS
O +
Ag O [1,5] shift H
O

Ag
Ag+

OTBS
OTBS
O
H O
Ag Ag+

Q29. Propose a mechanism for the following Achmatowicz rearrangement.

HO O

m-CPBA
O O

OH

Key 29.

HO HO OH
Hydroxy assisted O O
epoxidation aromatization
O O H+ OH
H+
O
O

OH
O
O
OH
H+

15
Q30. Suggest a two-step sequence for the following transformation.

Bn Bn
O O
O CHO O
CO2Me
N
H

Key 30. [1994 THN 7657 Moody CJ]

Bn
O
Bn
O CHO O
O
CO2Me
N
H
NaOme, MeOH,
Methyl azidoacetate

Xylene, heat

Bn
O
O
CO2Me

N3

Q31. Suggest a synthesis of

Br

N
N O

Key 32.

Cl Br N
H Br
Br Br
NH2OH.HCl Br2 N
OCHCO2H N Cl O N
OH NaHCO3 N O

16
Q33. Devise a synthesis of the meridianin A from an indole derivative as shown below.

N
NH2
O
OBn OH N

N Meridianin A
N
Ts H
Br

Key 33.

O
O OBn
OBn N H2N(=NH)NH2.HCl,
DMF-dimethyl acetal K2CO3

DMF, heat N
N Ts
Br
Br Ts

N N
NH2 NH2
OBn N OH N
H2, 10% Pd-C

N N
Ts H
Br

Q34. Devise a synthesis of the advanced intermediate shown below, required for the
synthesis of epiaustraline.

O
O
CO2Me epiaustraline
N MeO2C N
Boc Boc

Key 34.

17
 LiTMP,THF,
Li, NH3 COMe
78 C CO2Me
MeOC N OLi
N ClCO2Me MeO2C N
OLi Boc
Boc Boc

i) OsO4, Me3NO
ii) dimethoxypropane, O
O
NH4Cl CO2Me cat. PTS
N CO2Me
MeO2C N
Boc MeO2C
Boc

Q35. Suggest a viable synthesis of the following indole derivative.

CO2Me

N
H

Key 35. i) 1981 JCS Perkin 1636 Joule, JA; ii) 2010 CC 2823

CO2Me CO2Me Fischer Indolisation

AcOH cat. H2SO4
i) + Product
heat N N
N NH2 O
H H H

CO2Me H
ii) NH2 N
InBr3 FeCl3, K2CO3
+ Product
O CO2Me Cu(OAc)2, CuCl2

Q36. Propose a synthetic route for the following transformation.

HN Cl
CN
N
N NH2 N N
Ph Ph

18
Key 36. [2001 Org. Process Res. Dev. 581, Fischer RW]

CN
HN Cl

NH2 N
N
N N
Ph
Ph
HCO2H
OH Cl 3-chloroaniline,
ethanol
N POCl3 N

N N N
N

Ph Ph

Q37. Apply Povarov reaction to the synthesis of the following heterocycle in the
presence of a Lewis acid and write the structures of the required organic starting
materials.
CO2Me

NH

O O

Key 37.
CO2Me CO2Me
O
O
NH2 CO2Me N
+
O O OHC O O O O

Q38. Write the structure of the missing reactants, products and reagents in the following
scheme

19
 i) Et3N O
HO
H ii) [B] EtO [C]
[A] +
N OEt
EtO OEt N OEt O
O

Key 38. [1983 JOC 602 Ricca A]

EtO2C
EtO2C Cl EtO2C H
N N EtO OEt N OEt
OH O O
OEt
Et3N
(A)

[C] =
[B] = HO
EtO2C
Ca(AlH2(0-i-Pr)2]2.THF
HCl
N N OEt
O OEt O

Q39. Complete the following sequence of reaction with necessary reagents and
structures.
O [A] O O
[B] NH2 O
N N
N N CO2H N
CSNH2 Boc OEt
Boc S Boc S

O
NH2 O
N
N OEt
ethanol Boc S
[C]
heat
S
O
N
MeO2C

Key 39. [2007 SNT 954 Bagley MC]

20
A. i) Ethyl bromopyruvate, NaHCO3, Py, TFAA; ii) LiOH, MeOHH2O, rt

B. i) EtOCOCl, Et3N, THF, 0 C; ii) potassium ethyl malonatemethylmagnesium bromide, THF;

iii) NH4OAc, tolueneAcOH, MW

C.
S
MeO2C
N
O

Q40. Propose a plausible mechanism for the following rearrangement.

NH2
guanidine, heat
NC N
O H2N N N
H2N H

Key 40. [1995 JOC 6684 Taylor EC]

NH
N N
N
H2N NH2
H

HN O HN O O
H N

NH2 NH2

CHO
H2N NH2 H2N N
H

21