Cyclopropanes: A World of Wonders and BenefitsNew Methodologies

Armin de Meijere

Institut für Organische und Biomolekulare Chemie, Georg-August-Universität Göttingen,Tammannstr. 2, 37077 Göttingen, Germany

e-mail: Armin.deMeijere@chemie.uni-goettingen.dehttp://www.adm.chemie.uni-goettingen.de

Kassel, 8.05.2007

Organisch-Chemisches Institut, Universität Münster, 3. Juni 2009

1 Viktor Meyer (1876) doubts that they can exist at all.

2 August Freund (1882) and William Henry Perkin (1883–84) synthesize the first cyclopropanes.

3 Adolf von Baeyer (1885) rationalizes the enhanced reactivity of cyclopropaneson the basis of their inherent ring strain.

4 Since Ruzicka and Staudinger (1924) at the latest, every chemist knows that cyclopropanes exist in nature.

Small Rings

Small Rings

A. de Meijere et al. 1991–2005

Scientific curiosity, then and now

GDCh-Dia-1b

+NaOEt

Synthesis and ring opening: W. H. Perkin, Ber. dtsch. Chem. Ges. 1884, 17, 54–59.

"Strain theory": A. von Baeyer, Ber. dtsch. Chem. Ges. 1885, 18, 2269–2281.

EtOHBr

Br CO2Et

CO2Et CO2Et

CO2Et Br

CO2Et

CO2EtHBr

GDCh-Dia-2b

Old and New Natural Cyclopropane Derivates

CO2H

NH2

RCO2H

NH2

O

OH

OHIlludin SR = Me: norcoronamic acid

Inhibitors of the ethyleneforming enzyme

ACCPrecursor of the

phytohormone ethylene

N

O

H

NH

O2N

O

HNO

HNO

O HNO

HN

O ClNOH

NO2

ONH

NOO

Hormaomycin,a metabolite from

Streptomyces griseoflavuswith antimalerial activity

FR-900848, a fungicidal antibiotic

O

OH

OH

NHN

O

O

R = Et: coronamic acid a highly cytotoxicconstituent of Clitocybe illudens

N H

OU-106305

an inhibitor of the cholesteryl transfer protein

H2NCO2H

NH

OO

ONH

OBelactosin A, a potent proteasome inhibitor

Pyrethrin Ian insecticide

OO

O

RN H

N HN H

N HN H

N HOR'

OOOOOO

S. Abele, P. Seiler, D. Seebach, Helv. Chim. Acta 1999, 82, 1559.

S

N

CO2HO

N HR

O

NN

F

N

CO2HO

HN

F

N

F

F

CO2HO

N••

H2N

Trovafloxacin (PFIZER)a next generation

antiinfective

Ciprofloxacin (BAYER)a broad spectrum antiinfective

CIPROBAY ®

2.8 times more active thanAmpicillin (BEECHAM)

N. F. Osborne, J. Chem. Soc. Perkin Trans. I 1982, 1435.

To Model Nature or Even Surpass it

GDCh-Dia-3

[1] T. Liese, F. Seyed-Mahdavi, A. de Meijere, Org. Synth. 1990, 69, 148–153. [2] A. de Meijere, S. Teichmann, F. Seyed-Mahdavi, S. Kohlstruk, Liebigs Ann. 1996, 1989–2000.[3] A. de Meijere, S. I. Kozhushkov, T. Späth, Org. Synth. 2000, 78, 142–151. [4] A. de Meijere, S. I. Kozhuskov, D. Faber, V. Bagutskii, R. Boese, T. Haumann, R. Walsh, Eur. J. Org.

Chem. 2001, 3607–3614.For a review on strain energies in these compounds, see: A. de Meijere, S. I. Kozhushkov, A. F. Khlebnikov,

Top. Curr. Chem. 2000, 207, 89–147.

Reactive Small Ring Building Blocks for Various Applications

Krdia-340

CO2R

X

X = Cl,[1] F, OSiR3, SPh, N3,[2] NHZ

[3] [4]

SE = 41.7 kcal/mol SE = 77.4 kcal/mol SE = 74.6 kcal/mol

Methyl 2-Chloro-2-cyclopropylideneacetates from Tetrachlorocyclopropene and Alkenes

Review: A. de Meijere, S. I. Kozhushkov, L. P. Hadjiarapoglou, Topics Curr. Chem. 2000, 207, 149–227.

* Commercially available from Merck-Schuchardt** Preparation see: T. Liese, F. Jaekel, A. de Meijere, Org. Synth. 1990, 69, 144–147.

Krdia-277

Cl

ClCl

Cl

150–180 °C

ClCl

ClCl

Rm = H, alkyl, aryl, alkenyl, COR, CO2R, CN, CH2OR, CH2Cl SiMe3, CH2SiMe3, CH2OSiMe2But, OAc

R1

R4 R3

R2

60–80%(21–95%)

Cl

CO2MeR3

R4

R1

R2 ClCl

ClCl

1) NaOMe, MeOH110 °C, 1–3 d

2) H3O

up to 85%

Rn m

ClCl

ClCl CO2Me

Cl

* **Cl

ClCl

Cl

C2H4 (20 bar)C2Cl4, K2CO3

170 °C, 17 h

+

••

Krdia-412

A: SOCl2, NCS, cat. conc. HCl, 1,2-DCE, 85 °C, 15 h; B: SOCl2, NBS, cat. conc. HBr, 1,2-DCE, 85 °C, 15 h.

Advanced Syntheses of Cyclopropylideneacetates – Versatile Multifunctional Building Blocks for Organic Synthesis

M. Limbach, S. Dalai, A. de Meijere, Adv. Synth. Catal. 2004, 346, 760–766.

OMe

O

MeO

MeOEtMgBr (2.5 equiv.),

Ti(OiPr)4 (0.2 equiv.),Et2O, 0 → 20 °C, 12 h

OHMeO

1) MsCl, Py, CH2Cl2, 20 °C, 15 h2) cat. conc. HCl, H2O2, THF/H2O (2:1), 60 °C, 8 h

MeO

96% 74%

OMsHO

OBnOH, cat.pTsOH, toluene60 °C, 6 h

OMsBnO

O KOtBu, tBuOMe,0 → 20 °C, 18 h

97%H

O

BnO

1) A or B2) MeOH, 85 °C, 30 min

OMsMeO

O

X

NEt3, CH2Cl2,0 °C, 4 h

XO

MeO

X = Cl: 99%X = Br: 98%

X = Cl: 75%X = Br: 71%

83%

CO2MeOH Br

2 EtMgBrTi(OiPr)4

Ph3P Br2

Pyr., CH2Cl2

KOtBuDMSO

98% (crude) 78% 81%

90%

FVP350 °C

Bcpdia-13b

Versatile New Synthesis of Bicyclopropylideneand Methylenespiropentane

A. de Meijere, S. I. Kozhushkov, T. Späth, N. S. Zefirov J. Org. Chem. 1993, 58, 502–505.

A. de Meijere, S. I. Kozhushkov, T. Späth, Org. Synth. 2000, 78, 142–151.

A. de Meijere, S. I. Kozhuskov, D. Faber, V. Bagutskii, R. Boese, T. Haumann, R. Walsh,Eur. J. Org. Chem. 2001, 3607–3614.

Bcpdia-13b

R CO2Me2 EtMgBrTi(OiPr)4 HO

R

O. G. Kulinkovich et al. Synthesis 1991, 234.

ERC

CO2H

NH2

NH3+Cl–

HO2C

tBuP

tBu

Co

NH

COOEt

PhPh

X

Y X, Y = CO2Et

R2O2C R1

ER

R

E

H

O

R

( )

OHO

RN

n

X

R

O

Ar

ER

N=CPh2

Review:

Topics Curr. Chem.2000, 207, 89–147.

Bicyclopropylidene: A Highly Compact Multifunctional Building Block

Bcpdia-41

+ ArI +R1

R2

PPh3 (15 mol%)Pd(OAc)2 (5 mol%)

MeCN, Et4NCl, K2CO3 80 °C, 20 h

Ar R1

R2

ArPhPhPh

4-Tol4-Pyr4-Pyr CO2Me

HCO2MeCO2Me

HHR1 R2

CO2MeCO2tBuCO2MeCO2MeCO2tBuCO2Me

%100

8797998160

Ar

PdIAr

PdI

Ar

Domino Heck-Diels-Alder Reactions of Bicyclopropylidene with Aryl Iodides and Dienophiles

H. Nüske, S. Bräse, S. I. Kozhushkov, A. de Meijere, Chem. Eur. J. 2002, 8, 2350–2369. Pdc-053a

The Combinatorial Potential of the New Three-Component Reaction

H. Nüske, S. Bräse, S. I. Kozhushkov, A. de Meijere, Chem. Eur. J. 2002, 8, 2350–2369.

Pdc-089

I

XY

Acc2

YAcc1

+ +PPh3, Bu4NClPd(OAc)2

K2CO3, MeCN80 °C, 2 d

X

YAcc1

YAcc2

CO2Me

MeO

CONHtBu

Cl Cl

NPh

O

O

N

Cl

NMeN

O

O

MeO

CO2Me

NO2

N

CO2Me

(92%) (53%) (23%)

(81%)(40%)(55%)

Examples of Biologically Active Biaryls

PDC-187

NNHN N

OH3C

O

CO2H

CH3H3C

N

O

O

NCH3

H3C

NHON H

HNN

O

O

CH3

N CH3

OH3C

O

CH3H3C

SCF3

X

N

R2

R1

Antihypertensive Drug Gram-positive and Gram-negative inhibitor

Histamine H3 Receptor Antagonist LFA-1/CAM-1 antagonist Non-steroidal Anti-inflammatory DrugAntiarthritic

O

A. de Meijere, H. Nüske, M. Es-Sayed, T. Labahn, M. Schroen, S. Bräse, Angew. Chem. Int. Ed. 1999, 38, 3669–3672.

Combination of Cross-Coupling, Diels-Alder Reactionand Cross-Coupling with a Combinatorial Potential

I

NN

N

N

NN

N

N

Et4NClPd(OAc)2, PPh3

CO2Me

MeOH, (H2 for cPent), 2–12 hTFA, Pd(OAc)2 or Pd/C

= Merrifield resin

K2CO3, DMF80 °C, 2 d

CO2Me

CO2Me

R

Nor

3-cyclopentenylcyclopentyl(E)-2-pyridylethen-2-yl

786755

R %

Pdc-092

I,

HE E

43%

I,

E E E

E

35 °C

60%

E E

70 °C

49%

87%

PdI

PdI

A

A

E

E

70 °C

A : Pd(OAc)2, PPh3, NEt3, DMF, 80 °C, 4 h.

E

E

H. Nüske, S. Bräse, S. I. Kozhushkov, M. Noltemeyer, M. Es-Sayed, A. de Meijere, Chem. Eur. J. 2002, 8, 2350–2369.

An Inter-Intermolecular Domino of Heck and Diels-Alder Reactions

Pdc-052

PDC-056

Pd(0)-Catalyzed [3+2] Cycloadditions with Alkenes

MeO2C CO2Me

CO2Me

CO2Me

130 °C, 2 h54%

Pd(dba)2

P(iPr)2(tBu)

CO2Me

PhCO2Me

110 °C, 3 h58%

110 °C, 3 h81%

MeMeO2C Me CO2Me

MeO2C Ph Ph

+

+

+

74% 26%

90% 10%

89% 11%

P. Binger, P. Wedemann, S. I. Kozhushkov, A. de Meijere, Eur. J. Org. Chem. 1998, 113–119.

A New Sequence for the Generation of Five-Seven-Ring Combinations

A: Pd(dba)2, P(iPr)2(tBu), toluene, 110 °C, 3 h. – B: 2-Butyne, [RhCl(PPh3)3], AgOTf, toluene, 110 °C, 3 h.

P. Binger, P. Wedemann, S. I. Kozhushkov, A. de Meijere, Eur. J. Org. Chem. 1998, 113–119.

PDC-059

E EE E

E

E+

A

83%

B

51%

E = CO2Et

An Unexpected [2+3+2]Cocyclization of Bicyclopropylidene with an 1,6-Enyne

PDC-200plt

EE

EE

E

E

Ni(cod)2 (10 mol%)PPh3 (20 mol%)

toluene, r. t.+

E = CO2Et

83%

not found

L. Zhao, A. de Meijere, Adv. Synth. Catal. 2006, 348, 2484–2492.

PDC-201plt

[2+3+2] Cocyclizations of Bicyclopropylidene with Terminal Alkynes

L. Zhao, A. de Meijere, Adv. Synth. Catal. 2006, 348, 2484–2492.

2 ×

PPh3Ni

PPh3 PPh3NiPPh3

R

PPh3Ni

PPh3R

PPh3

Ni PPh3R

Ni(cod)2PPh3

toluener. t.

R R

R

tBuMe3SiCpr(Me)CprPhnBuHOEtCO2MeCH2OH 25

85777656592879293

Product (%)

PDC-199

Yet another [2+2+2]Cocyclization of Bicyclopropylidene and Internal Alkynes

R

R

+Ni(cod)2, PPh3

C6H6, r. t.

R

RNiL2

CH2OMePhCprR %

362573

L. Zhao, D. Frank, A. de Meijere 2006

Nitrone Cycloadditions to Methylenecyclopropane and Bicyclopropylidene

A. Brandi, A. Goti, S. Kozhushkov, A. de Meijere, J. Chem. Soc. Chem. Commun. 1994, 2185.C. Zorn, B. Anichini, A. Goti, A. Brandi, S. I. Kozhushkov, A. de Meijere, L. Citti, J. Org. Chem. 1999, 64, 7846–7855.

Bcp-006

R2 O–N+

R1

+ON

R2

R1

NR2

R1 O

Me O–N+

Ph+

ONMe

Ph

NMe

Ph O60 °CC6H6

110 °CC6H5Me

63%93%

N+ +O–

80%ON

76%N

O

Review: A. Brandi et al. Synlett 1993, 1.

69–86% 50–60%

65–90%+ regioisomer

35–10%

1,3-Dipolar Cycloadditions onto Bicyclopropylidene

B. Anichini, A. Goti, A. Brandi, S. I. Kozhushkov, A. de Meijere, Synlett 1997, 25–26.

Bcp-029

N

H OtBuO

tBuO

NO

xylenes120 °C, 10 h

tBuO

NO

xylenes120 °C, 10 h

OtBu

N

H OtBuO

OtBu

ON NO • • N

••

O

66% 61%

Krdia-440

1,3-Dipolar Cycloadditions of Nitrones to Methylenecyclopropanes and Possible Subsequent Transformations

For n = 0 see: F. M. Cordero, F. Pisaneschi, A. Goti, J. Ollivier, J. Salaün, A. Brandi, J. Am. Chem. Soc. 2000, 122, 8075–8076.

n = 0, 1

ON

R1

R2

n+ –

+R1

R2 NO

n = 0, 1

n

n

OR2N

R1

n = 0, 1

Δ, H+

NR2

OH

OR1

H

n = 1

Spirocyclopropanated β-Lactams from Nitrones and Bicyclopropylidene

Krdia-441

A. Zanobini, M. Gensini, J. Magull, S. I. Kozhushkov, A. de Meijere, A. Brandi, Eur. J. Org. Chem. 2004, 4158–4166.

ON

R1

R2+ –

R1

R2 NO

1OR2

N

R1C6H6, 20–60 °C

2–36 d71–100%

MeCN, TFA

70 °C, 0.5–12 h75–96%

PMB = p-methoxybenzyl

1abcdef

R1

CO2MePhCNCNPh2-Py

BnBnBnPMBMeMe

R2 2abcdef

%

1009594

1009371

3abcdef

%

787575949696

2 3

One-Pot Synthesis of Spirocyclopropanated β-Lactams –A New Three-Component Reaction

A. Zanobini, A. Brandi, A. de Meijere, Eur. J. Org. Chem. 2006, 1251–1255.

Krdia-444

+RNHOH • HCl

+CH2O (aq.)

NaOAc, EtOH100 °C (MW)

1 hN

R O

R

Bnp-MeOBn

CHPh2

%

685349

+

R1NHOH • HCl+

HOR2

O

O

NaOAc (2 equiv.)EtOH, 80 °C

(MW), 15–105 min NR1 O

EtOO

2 equiv. each

1 equiv.

R1

BntBuPMB

R2

EtEtMe

%

725378

A. Zanobini, M. Gensini, J. Magull, S. I. Kozhushkov, A. de Meijere, A. Brandi, Eur. J. Org. Chem. 2004, 4158–4166.

Krdia-443

Dipeptides from Spirocyclopropanated N-Acyl-β-lactams 4

NR3 NOtBu

OR1

H

O

H O

ONR1

R3 O(or 7)

DMF, 60 or 152 °C

tBuO2C NH2·HCl7·HCl (R4 = H) or

4b, 6

ONMeO2C

O

4a

DMF, 152 °C, 20 h

tBuO2C NH27

51%

O

N ON

OtBuO

HO

8

10–12

R4

R4

12–70 h

Starting Material4b66

R1

PhCNCN

PhOtBuOtBu

R3 R4

HHBn

%

6184

Product

101112

9·HCl (R4 = Bn), NEt3

81[a]

[a] Diasteromeric ratio 1:1.1

Two Possibilities to Obtain Heterocycles from 2-Chloro-2-cyclo-propylideneacetates and a Bisnucleophile

A. de Meijere, I. D. Kuchuk, V. V. Sokolov, T. Labahn, K. Rauch, M. Es-Sayed, T. Krämer,Eur. J. Org. Chem. 2003, 985–997.

Krdia-346

CO2R

¯Y

HZ+

Y

Z¯

Y

RO2C ZO

Y

Cl Z

Cl Cl CO2R

M. W. Nötzel, M. Tamm, T. Labahn, M. Noltemeyer, M. Es-Sayed, A. de Meijere, J. Org. Chem. 2000, 65, 3850–3852.

2-Chlorocyclopropylideneacetate Reacting with Aroylamides

Krdia-067

CO2Me

Cl+ H2N Ar

ODMF, –10 → 20 °C1 eq NaH

24 h O

CO2Me

N Ar NPh

CO2MeOH

H O2) 5 M NaOH, PhCOCl1) 1 N HCl, 100 °C

Ar = Ph, 66%

O

CO2Me

N

E

+

O

MeO2C

N

N

O

CO2Me

E,Pd(OAc)2,

NEt3, PPh3DMF, 80 °C, 24 h

Ar =C6H4-2-IAr

PhC6H4-2-OMeC6H4-4-BrC6H4-4-CNC6H4-2-ClC6H4-2-IC6H4-3-FC6H4-2-NO2

%

5069786679747638

25%

56%

M. W. Nötzel, T. Labahn, M. Es-Sayed, A. de Meijere, Eur. J. Org. Chem. 2001, 3025–3030.

Thiazoline-4-carboxylates and Cysteine Derivatives Incorporating Cyclopropyl Groups

Krdia-342

CO2Me

ClR1 +

R2 NH2

S S

N

R2

CO2Me

NaHCO3, MeCN80 °C, 2−5 h

SR2 NH

CO2MeCl

R1 R1

37–92%20 examples

R1

HHHHHMeMeEt

(CH2)2OBn

R2

PhMe4-Br-Ph4-MeOC6H4NMe2PhMeMeMe

Yield (%)

867385534951527877

D. R.

—————

1.2 : 11.9 : 1

1.7 : 1 : 11.1 : 1

S

N

Me

CO2Me

N H

SH

MeO2C

OSH

CO2HNH3Cl

3 N HClΔ, 3 h

H2OΔ, 5 h

89%93%

Cyclobutene-Annelated Pyrimidinones from 2-Chloro-2-cyclopropylideneacetates and Amidines

M. W. Nötzel, T. Labahn, K. Rauch, A. de Meijere, Org. Lett. 2002, 4, 839–841. Krdia-343

+HN NH2

R

N

NH

REt3N, dioxane25 °C, 2 d

CO2Me

N

CO2Me

N

R

CO2Me

N R

NH2

Cl NH2

R

–MeOH

O

NH2N

NH2R

CO2MeCl

CO2Me

Cl

Cl

R

HPhp-Me-PhNMe2NH2

Yield (%)

57847959–[a]

a Decomposition

Cyclobutene-Annelated Pyrimidinones as Heteroanalogues of Benzocyclobutenes

M. W. Nötzel, T. Labahn, K. Rauch, A. de Meijere, Org. Lett. 2002, 4, 839–841.

Krdia-344

R2 R3

R4R1

+170 °C,

8 hNH

N Ph

O

NH

N Ph

O

R3

R2

R4

R1NH

N Ph

O

R4

R1

R3

R2

+

R1

CO2MeCNCO2MeCO2MeCO2Me

R2

HHH

CO2MeH

R3

HH

CO2MeHPh

R4

HHHHH

Yield (%)78478473[a]

82[b]

Ratio2.4:1

2:1——2:1

[a] Mixture of cis- and trans-dicarboxylate in the ratio of 4.8:1. – [b] Pure trans-isomer.

N

NH

Ph

O

Ti(OiPr)4MgBr

R3

(iPrO)2Ti

R3

R3

(iPrO)2Ti

R3

R3

OR2

O

R1

MgBrR3

2

O(iPrO)2Ti

R1OR2

R3MgBr

R3

R3

R1 O(iPrO)2Ti

R3

R3

R1 OMgBr

2 iPrOMgBr

R3

R1 OH

H2O+

NR2 2

O

R1

MgBrR3

NR2 2

R1R3

R1

O

R3

(iPrO)2Ti

R3

Ti(OiPr)4,

?

Mechanistic Considerations of the Titanium-Mediated Cyclopropanation of Esters

The originalKulinkovich protocol:[*]

[*] O. G. Kulinkovich, S. V. Sviridov,D. A. Vasilevski, Synthesis 1991, 234.

Our adaption:[**]

[**] V. Chaplinski, A. de Meijere,Angew. Chem. Int. Ed. Engl. 1996, 35, 413–414.

Krdia-214n

NR2 2

O

R3MgBr

+Ti(OiPr)4

R3

R1

NR2 2

O(iPrO)2Ti

R3

R1

NR2 2

(iPrO)2Ti

R3

2 THF, –78

[(iPrO)2Ti=O]n

R3

(iPrO)2Ti

R3

NR2 2R1O

R1

NMe256%

NBn251%

ON

74%

N(iPr)276%

N(tBu)2

20%NBn2

69%

→ 20 °C

–

+–

A Versatile Synthesis of Cyclopropylamines

V. Chaplinski, A. de Meijere, Angew. Chem. Int. Ed. Engl. 1996, 35, 413–414. See also: Chem. & Engineering News "Science Concentrates" 19. Feb. 1996.

Krdia-057e

NN

F

N

CO2HO

N

F

N

F

F

CO2HO

Trovafloxacin (PFIZER)Ciprofloxacin (BAYER)CIPROBAY ®

Three examples are broad-spectrum antibiotics:

N••

H2NH

TROVAN ®

F

N

CO2HO

MeONN

H

Moxifloxacin (BAYER)AVALOX ®

The Patent Literature Lists 191 Pharmacologically RelevantCompounds with Cyclopropylamine Moieties

Krdia-163

R1 NR2 2

O

R3MgBr

+

MeTi(OiPr)3

R3

R1

NR2 2(iPrO)2Ti

R3

THF

CH4

R1 R2 R3 %

51 (38)a

86

Me

VinBn

BnEt

H

a Yield with Ti(OiPr)4r. t.

NBn2NBn2 NBn2

2c2b 2d

cdef

H

H

Bn

Bn

Me

H

89

95

E/Z

1.1:16.5:1

1 2 ba

Et Bn H 7077HBnMe

V. Chaplinski, A. de Meijere, Angew. Chem. Int. Ed. Engl. 1996, 35, 413–414.

Modified Reagent and Conditions for the Cyclopropanation of Dialkylamides

Krdia-070

NBn2R

O1.2 eq MeTi(OiPr)3

2.0 eq EtMgBr

r. t. NBn2R

H NBn2O

NBn2 NBn2

NBn2

O

NBn2

NBn2

O

NBn2

NBn2

O

H

NBn2

O

NBn2

NBn2

O

NBn2

NBn2

O

NBn2

Amide Cyclopropylamine Yield (%)

>95

77

70

62

44

25

52

Harald Winsel, Markus Kordes 1997–98

Influence of the Substituent on the Carbonyl Group I

Krdia-206

NBn2R

O1.2 eq MeTi(OiPr)3

2.0 eq EtMgBr

r. t. NBn2R

H NBn2

NBn2

NBn2

NBn2

NBn2

NBn2

Cyclopropylamine Yield (%)

>95

77

70

62

44

25

Cyclopropylamine Yield (%)

47

63

<10

49

48

38

NBn2Cl

NBn2Ph

NBn2BnO

NBn2Cl

NBn2Ph

NBn2BnO

NBn2

+

3 : 1

Influence of the Substituent on the Carbonyl Group

Harald Winsel, Markus Kordes 1997–98 Krdia-206a

Grignard Reagent Cyclopropylamine Yield (%)

79

81

86

DiastereomericRatio

MgBr

MgBr

MgBr

MgBr

1 : 6.0

1 : 1.6

NMe2(MeO)2PO

NMe2(MeO)2POO 1.2 eq MeTi(OiPr)3

r. t.

MgBr2.0 eq R

R

NMe2(MeO)2PO

NMe2(MeO)2PO

NMe2(MeO)2PO

NMe2(MeO)2PO 82 1 : 1.4

R

H

Me

Vin

Ph

Versatility of the Method

H. Winsel, V. Gazizova, O. Kulinkovich, V. Pavlov, A. de Meijere, Synlett 1999, 1999–2003.Krdia-211

Reductive Cyclopropanation of Lactames

Krdia-273

O

N N + MeNHOH

EtEtMeTi(OiPr)4 (1 equiv.)EtMgBr (1.1 equiv.)

THF, 24 h

O

NBn

NBn

BnNH

OHEt

Et+

Ti(OiPr)4 (1 equiv.)EtMgBr (2 equiv.)

THF, r. t., 24 h

A. de Meijere et al. Synlett, 1997, 111–114.

O

N

Ph O

O

N

Ph

N NO

as above

EtMgBr,Ti(OiPr)4

THF, r. t., 15 h

52%

Cotinin

28% 56%

47% 3%

77%

N N

B. Stecker, M. Es-Sayed, A. de Meijere 2000

Simple Access to 6-Amino-3-azabicyclo[3.1.0]hexane – A Bicyclic DiamineScaffold for Combinatorial Synthesis of Lead Compounds

A. de Meijere et al. Chem. Eur. J. 2002, 8, 3789–3801.

Krdia-166a

NPG + +NBn2

HO MeTi(OiPr)3

THF

Et2OTi(OiPr)4 + MeMgCl

(3 Ti(OiPr)4 + TiCl4) + MeLi

cHexMgBr (2.5 equiv.)THF/Et2O0 → –5 °C, 50 minreflux, 15 minor r. t. 8 h

•NBn2N

•PG

•NH2N

•Boc

•NH2HN

•

•NBn2HN

•

N N 4.28 Å(X-ray)

93% (cryst.)

98%

98%

PG = Bn:PG = Boc: 90%

87% CF3CO2H, r. t.polym. base

PG = Boc

PG = Boc

PG = Bn

H2, Pd/C (1.7 mol%)MeOH, HOAc (5%)

H2, Pd/C (3 mol%)MeOH

Krdia-166b

A. de Meijere et al. Chem. Eur. J. 2002, 8, 3789–3801.

A Simple Access to exo-6-Amino-3-azabicyclo[3.1.0]hexane – The Mechanism

+ MeTi(OiPr)3 Ti(OiPr)2MgBr

NPG

Ti(OiPr)2NPG •NR2NPG

•

CH4

NR2

HO

up to 90%PG = Bn, Boc

N

HO

OtBu

O

Boc

1) PPh3, DIAD, MeI

2) DBU, C7H8, 85 °C, 8 h NOtBu

O

Boc

H NBn2

O

N

••

NBn2

Boc

MeTi(OiPr)3c-C6H11MgBrTHF, 17 h

OtBu

O

••O

N

R3O

N H

HNR1

ON H

HNO

R2

HN

THF, 0 °C → RT, 17 h

69% 49–51%+regioisomer

Easy Access to 3,4-(Aminohomo)proline as a BuildingBlock for New Hair-Pin Peptidomimetics

Farina Brackmann, Armin de Meijere 2003–05

N N4.25 Å

Krdia-398

Coworkers

Collaborations

Financial SupportGeorg-August-Universität Göttingen Studienstiftung des Deutschen Volkes(State of Niedersachsen) Alexander-von-Humboldt StiftungVolkswagen-Stiftung Deutscher Akademischer AustauschdienstDeutsche Forschungsgemeinschaft European UnionFonds der Chemischen Industrie

Bicyclopropylidenes andTriangulanes

Thomas Späth Baris YucelStefan Bräse Rafael R. KostikovHanno Nüske Alexander F. KhlebnikovRene Scheurich Sergei I. KozhushkovLars Arve

Pentacyclopropyl-cyclopentadiene

Ingo EmmeStefan Redlich

Vladimir Chaplinski Andrei SavchenkoAlexandre Kourdjoukov Björn SteckerSergei Sviridov Stefan WiedemannMarkus Kordes Christian StratmannCraig M. Williams Oleg LarionovHarald Winsel Boris Zlatopolski

CyclopropylaminesAnd More

Chemistry Computations X-ray Crystal StructuresMazen Es-Sayed, BAYER AG Peter R. Schreiner, Gießen Roland Boese, Essen Hans-Ulrich Siehl, Ulm Dimitri S. Yufit, DurhamIlan Marek, Haifa George Sheldrick, GöttingenAxel Zeeck, Göttingen Jörg Magull, GöttingenStefan Bräse, KarlsruheKazutoshi Miyazawa, Chisso Corp.

Coworker