Domino

Reactions
By
Asmaa Abouzaid
Teaching Assistant at Zewail City
 What’s the Domino Effect
Take a number of dominoes and build a row by standing them on
end with only a small distance in between. If you do it right, you
can tip the first domino and cause all others to fall down in
succession
Difference Similarities

cascade
reaction

tandem
reaction

domino
reaction
 Similarities of Cascade,
Tandem and Domino
reactions
General • Are a consecutive series of intramolecular organic
1 reactions which often proceed via highly reactive
Definition
intermediates.
• One-pot reactions: Without isolation and purification of
products.
• provide specific targeted molecule of considerable
structural and stereochemical complexity
 In organic synthesis (called green chemistry) are that
• the reaction is often fast due to its intramolecular nature
• the reaction is also clean
Main • displays high atom economy
2 Advantages • does not involve workup and isolation of many
intermediates
• Dramatic increase in molecular complexity.
• Save material, time, labor, energy, resource and waste
management.
• Beneficial effect on the environment by avoiding of toxic reagents
as well as toxic solvents

• New natural product synthesis.

3 Application • Synthesize fused and caged ring system.
• Quaternary stereocenter forming
• Protecting group and functional group changing
Difference

Cascade reaction

• Meaning: if water molecules are examined as they cascade, they

are simply moving and do not change
• Two or more bonds are formed. Latter transformations take place
at the functionalities obtained in the former-bond forming process
• General Used in so many different connections
• − for example, photochemical cascades, biochemical cascades or
electronic cascades
• The time-resolved aspect with “cascade reactions” As domino
process
 Example Cascade but not Domino: Vitamin B12 (called cobalamin,
is a key role in the normal functioning of the brain and nervous system, and the
formation of red blood cells) With genetically engineered 12 enzymes

.Ala derv
 Tandem reaction

• Meaning: as “locally, two after each other”, as on a tandem bicycle or

for tandem mass spectrometers
• Several bonds are formed in sequence, without isolating intermediates,
changing reaction conditions, or adding reagents
• the term “tandem” does not fit with the time-resolved aspects of the
domino reaction type; moreover, if three or even more bonds are
formed in one sequence the term “tandem” cannot be used at all
Example Tandem but not Domino: Chlorothricolide (antibacterial
agent against Gram-positive )
Intramolecular and intermolecular reaction in a same step

1,3 Dioxalane derv

hexaenoate

Trichloro ethylene
 Key Reactions
• is specifically, a [4+2] cycloaddition(types of pericyclic
Diels–Alder reaction)
reaction • between a conjugated diene and a substituted alkene,
commonly termed the dienophile, to form a
substituted cyclohexene system
 Domino
reactions
• is a process involving two or more bond-forming
transformations (usually C-C bonds) which take place
Definition under the same reaction conditions
• without adding additional reagents and catalysts
• in which the subsequent reactions result as a
consequence of the functionality formed in the previous
step.
• are time-resolved transformations, an excellent
illustration being that of domino stones
 First domino :Tropinone by Robinson at 1917
synthesis synthetic precursor to atropine (pesticide poisonings)

Biomimetic synthesis of Progesterone by cationic polyolefin cyclization by

Johnson at 1971:
Me Me
O Me O O
Me O Me Me
Me Me H H
Me O O
O Me K2CO3 Me
Me O Me
Me MeOH/H2O
Me
H H H H
TFA H H
DCE, 0°C Me O
HO Me
Me 71% yield (+/-)-Progesterone
Me
17/17 : 1/5
 Classification of domino
reactions
Depends on used the mechanism of the different bond-
forming steps

1. Nuchlophilic Dominoes 5. Transition metal Dominoes

2. Electrophilic Dominoes 6. Photochemical Dominoes
3. Radical Dominoes 7. Oxidative or reductive Dominoes
4. Pericyclic Dominoes 8. Enzymatic Dominoes
 1 Nuchlophilic Dominoes

Initiated by nucleophilic attack(As Common initiator) :

• Conjugated addition
• SN2 substitution
• Grignard reaction …..
Homo domino process Hetero domino process

(Another nucleophilic attack) In which a succession of cationic (by a

pericyclic step or arrangement)
• Pericyclic process: oxy-Cope, [3+2]
• Rearrangements: Brook rearrangement,
B-V rearrangement
 Key Reactions
First step:
is the nucleophilic addition to an α,β-unsaturated
Conjugated addition carbonyl compound (Enone : good electrophile)
(Michael addition) And formed of enolate intermediate (Enol : good
nucleophile with competition between C- and O-
attack)
R1 O
Nu
R2 R3
R1 O Nu R1 O E
Nu E
R2 R3 R2 R3
E
R1 O
Nu
R2 R3
second step
(intramolecular) condensation, SN2 reaction, or another Michael process.
 Example 1 Ley’s total synthesis of Tetronasin (1998)

Me
O Me
O
MeO Pot.bis (triMe silyl)amide MeO
Me
HO Me
O
Me KHMDS (1.1eq)
Me
O
K
Me H H OMe Toluene, 0°C, 30min O
O Me H H OMe
O
Me OMe
Me Me OMe
Me

Me
Me
HO MeO2C
Me
H OH Me
H OH
Me
Me Me
O
Me H ONa Me H H OMe Me O
O Me H Me H H OMe
CO2Me
Tetronasin 67%-86% yield
O O
 Dimerization of (+)-Avrainvillamide in (-)-Stephacidin
Example 2
(Myers and Baran, 2005)

O
MeMe O O H O
N H Me
N MeMe O MeMe OH
Me N H Me N H Me
N N
O Me Me
O N
O O
H Et3N O N N
O
MeCN, rt H H
H O N O N
O N O O
O
Me Me
Me
N N N Me N N Me
N Me H H
H MeMe O H MeMe O
MeMe O
O O
O
H (-)-Stephacidin B
(+)-Avrainvillamide
2 Electrophilic Dominoes

• Initiated by a electrophilic attack.

• Based on rearrangements of carbocation.
• Usually Prins reaction, Mannich reaction and
rearrangements followed.
• Finally being quenched by a nucleophile or
stablized by elimination of a proton.
• Cationic cyclization: Biomimetic synthetic route
for complicated alkaloids and terpenoids
 Enamine-Iminium

Enamine : good nucleophile

Iminium : good electrophile

R1 R2 R1 R2
N H or E N R1 R2
Nu N
R4 R4
R3 R3 R4
Enamine R3
E Nu
E
Iminium
 Example 1 Corey’s total synthesis of (-)-Aspidophytine (1999)

O CO2iPr
NH2 NH CO2iPr N CO2iPr N H
O OHC
MeCN, 23°C, 5min Pictet-Spengler
TMS TMS TMS
CO2iPr Then TFAA, 0°C, 2h
MeO N N N MeO N
MeO MeO
OMe Me TMS OMe Me OMe Me OMe Me

O
N H CO2iPr
N H CO2iPr CO2iPr
N O N H
H
NaBH3CN

MeO N H N H
N H MeO MeO N H
MeO OMe Me OMe Me OMe Me
OMe Me
66% yield
(-)-Aspidophytine
 a chemical reaction in which a β-arylethylamine such as
Pictet– tryptamine undergoes ring closure after condensation
Spengler with an aldehyde or ketone. Usually an acidic catalyst is
reaction employed and the reaction mixture heated
 Example 2 Heathcock’s total synthesis of dihydro-proto-daphniphylline (1992)

R Me Me
R
R R H R
O H
enamine H
O 1) MeNH2 O 1,4-addition formation
N Me
Me N R
2) AcOH,  Me Me N
O N R Me
NH2 R
H Me NH2 R
R R Me
N
Me

hetero-
Diels-Alder
R
R R R
Me H
Me H Me H H
hydrolysis 1,5-hydride shift aza-Prins Me
Me HN
Me N Me N Me N
Me
65% yield H
Dihydro-proto-daphniphylline
 is an organic reaction consisting of an electrophilic
addition of an aldehyde or ketone to an alkene or alkyne
Prins reaction
followed by capture of a nucleophile
 3 Radical Dominoes
Radical cyclization

Reactivity
(Baldwin rules)

Radical precursor
Alkyl radical cyclization /1

Example 1 Curran’s total synthesis of (+/-)-Hirsutene (1985)

Br
Me nBu3SnH (1.2eq) Me
Me AIBN (cat.) Me
Me Me
benzene, 80°C
H H H H
1) 5-exo-trig
2) 5-exo-dig

Me H Me Me H Me

Me Me

H H H H
61% yield
(+/-)-Hirsutene
Aryl radical cyclization /2
Fokas and Parker’s total synthesis of (-)-Morphine
Example 2
SPh SPh

nBu3SnH (1.5eq)
Br Ts AIBN (cat.) 5-exo-trig
Ts SPh
N N O
MeO O Me benzene, 130°C, 35h Me
MeO O
HO N Ts
HO HO Me

6-endo-trig

O H
O H O H
SPh
HO N
Me HO N Ts HO N Ts
(-)-Morphine Me Me
30% yield
 4 Pericyclic Dominoes

1- Diels-Alder reaction

O O
2- Claisen rearrangement 
R1 R1
R2 R2

X  X
3- Cope rearrangement X: CH3, OH
1/ [4+2] / [3+2] arrangement

Boger’s total synthesis of (-)-Vindorosine (2006)

Example 1

O
O O
N
Me (iPr)3benzene (0.1mM) N Me N Me
N 230°C, 5-6d
N O O
N N OBn -N2 O
O hetero-Diels-Alder N N OBn
Me N
CO2Me Bn Me Me

1,3-dipolar
cycloaddition
O
N N
Me Me
H O
N H OAc N H OBn
Me OH CO2Me Me CO2Me
(-)-Vindorosine 78% yield
 ene / ]3,3[ / ]3,3[ /2

Barriault’s synthesis of Wiedemannic Acid skeleton (2004)

Example 2
H
Me microwave Me
O O
O toluene, 210°C OTBS OTBS

OTBS oxy-Cope rear. Claisen rear.

Me H Me Me H Me Me H Me

carbonyl-ene

O H H
OH CO2H
Me OH
OTBS
Me
H Me
H Me H Me
Wiedemannic Acid 90% yield - dr=25/1
 5 Transition-Metal-
1/ Palladium-Cu Catalyzed Dominoes
Example 1 Schreiber’s total synthesis of Dynemicin A (1993)
Cu MeO O
Pd(PPh3)4 (2%)
MeO O H N
CuI (20%) MeO O
amine base Me
N N OMe
toluene, rt, 2h L Br
Br O Pd O Pd
OMe OMe
L
O Me O Me O
O

HO MeO O
MeO O
O H N
OH H N
H
H N Me
O Me OMe
Me OMe
OH H transannular
O H
H Diels-Alder O
HO2C H H
O O
OMe O
25% yield
Dynemicin A single dia
2/ Ruthenium cat.
Hanna’s formal synthesis of (+/-)-Guanacastepene A (2004)
Example 2
CO2Me Ph Me
CO2Me CO2Me Me
CO2Me
Grubbs 2nd Ru Ru
generation Ru
Me
(12mol%) Me Me
Me Me
Me Me Me Me
CH2Cl2, reflux, 3h Me Me Me
Me
Me Me Me
Me Me Me Me
Me Me

Me
Me Me
OH MeO2C Ru Me
OHC MeO2C Ru
MeO2C
O
Me Me Me Me
AcO
Me Me Me Me
Me Me Me Me Me Me Me Me
(+/-)-Guanacastepene A 82% yield - dr=1/1
 6 Photochemical Dominoes
Photochemical reactions usually proceed via an excited electronic state. Unique
products can therefore be obtained, which are not accessible by thermally induced
transformations

Example Stypoldione (bovine brain disease)

 7 Oxidative or reductive
Dominoes
Example Vasicinone (antiallergic agent)

TBAF: Tetra-n-
butylammonium
fluoride)

Silyl ether
 8 Enzymatic Dominoes
• Nature enzymes which are able to catalyze a multitude of different
transformations with amazing enhancements in rate

• Moreover, these enzyme proteins show a high specificity in most cases,

allowing the enantioselective formation of chiral compounds.

• Enzyme-triggered domino reactions follow a common scheme. Initially, the

enzyme modifies a so-called “trigger” group in the starting material, furnishing
a reactive species that can undergo a subsequent domino reaction.
• the reactive group created in the first step may be a diene or dienophile (the
latter generated, for example, by the oxidation of an allylic alcohol)
Example

oxidation
Diels- Alder
 Disadvantages

• Almost only thermodynamic stable product occurs.

• Often take time to find suitable precursors and conditions to

obtain the desired domino reaction (reduce the economy
advantage…)
 Dominoʼs Future

• Enantioselective
• Multicomponent
• Organometallic
"We need to set a time line, at which any natural
products can be synthesized in less than 5
steps...”