A2.7.4 PROCEDURE FOR ATTEMPTED REACTIONS WITH 2- (CHLOROETHYL)ISOCYANATE

These reactions were carried out using our standard procedure. See General Procedure D, Experimental Section, Chapter 2. In no case did analysis of the reaction mixture and crude product by TLC, LCMS, and NMR show anything other than decomposition products.

MeO MeO

252 CO₂Me

CO₂Me NCO

Cl 253

FeCl3 or Sn(OTf)2

CH₂Cl₂, 23 °C

MeO

MeO N

Cl

O

MeO₂C CO₂Me 251

195 CO₂Me

CO₂Me NCO

Cl 253

FeCl₃ CH₂Cl₂, 23 °C

N Cl

O

MeO₂C CO₂Me 254 Cl

Cl

The reaction of cyclopropane 252 with allyl isothiocyanate was carried out using our standard procedure. See General Proceedure F, Experimental Section, Chapter 2.

Analysis of the reaction mixture and crude product by TLC, LCMS, and NMR showed only decomposition.

dimethyl (E)-5-(3,4-dimethoxyphenyl)-1-isopropyl-2-(isopropylimino)pyrrolidine- 3,3-dicarboxylate (256):

The reaction of cyclopropane 252 with diisopropylcarbodiimide was carried out using our standard procedure. See General Proceedure G, Experimental Section, Chapter 2.

Analysis of the reaction mixture and crude product by TLC, LCMS, and NMR showed only decomposition.

¹

H NMR analysis (300 MHz, CDCl

3

) of the crude product (256) showed signals correponsing to the 5-arylamidine ring: δ 5.19 (dd, J = 8.4, 3.7, 1H), 3.23 (dd, J = 13.7, 8.5, 1H), 2.69 (dd, J = 13.7, 3.7, 1H). Further purification was not attempted.

MeO MeO

252 CO₂Me

CO₂Me NCS

Sn(OTf)₂ CH₂Cl₂, 23 °C

MeO

MeO S

N

MeO₂C CO2Me 255

MeO

MeO

252 CO₂Me CO2Me

Sn(OTf)₂ CH₂Cl₂, 23 °C

MeO

MeO N

N

MeO₂C CO₂Me

256

NC

i-Pr N

i-Pr

i-Pr i-Pr

The reaction of cyclopropane 252 with benzyl isocyanate was carried out using our standard procedure. See General Proceedure D, Experimental Section, Chapter 2. A mixture of 257 and 258 was obtained, and the following characterization data was collected. 257 (47% yield):

¹

H NMR (300 MHz, CDCl

3

) δ 7.31–7.27 (m, 3H), 7.10–7.06 (m, 2H), 6.87 (d, J = 8.2, 1H), 6.72 (dd, J = 8.2, 2.1, 1H), 6.63 (d, J = 2.1, 1H), 5.11 (d, J

= 14.5, 1H), 4.33 (t, J = 7.6, 1H), 3.93 (s, 3H), 3.89 (s, 3H), 3.85 (s, 3H), 3.84 (s, 3H), 3.55 (d, J = 14.6, 1H), 2.97 (dd, J = 13.9, 7.3, 1H), 2.69 (dd, J = 13.9, 7.9, 1H).

¹³

C NMR (126 MHz, CDCl

3

) δ 167.9, 167.8, 167.0, 149.6, 149.2, 135.5, 130.7, 128.7, 128.5, 127.8, 120.1, 111.1, 109.7, 63.3, 58.6, 56.0, 55.9, 53.6, 53.5, 45.2, 37.8. 258 (40% yield):

¹

H NMR (300 MHz, CDCl

3

) δ 7.37 (s, 1H), 7.35–7.24 (m, 5H), 6.80 (d, J = 0.6, 1H), 5.33 (d, J = 15.3, 1H), 4.42 (dd, J = 4.2, 3.3, 1H), 4.09 (d, J = 15.3, 1H), 3.98 (s, 3H), 3.94 (s, 3H), 3.72 (s, 3H), 3.49 (s, 3H), 2.88 (dd, J = 6.9, 6.3, 1H), 2.77 (ddd, J = 15.1, 7.0, 4.4, 1H), 2.60 (ddd, J = 15.0, 6.2, 3.2, 1H).

¹³

C NMR (126 MHz, CDCl

3

) δ 169.5, 169.5, 169.0, 152.7, 150.0, 137.0, 136.6, 128.8, 128.1, 127.6, 125.0, 105.4, 104.9, 56.4, 56.3, 56.3, 53.0, 52.6, 45.5, 43.8, 29.0.

MeO MeO

252 CO₂Me CO₂Me

FeCl3

CH2Cl2, 23 °C

MeO

MeO N

O MeO₂C CO₂Me

NC

Bn O Bn

MeO + MeO

N Bn CO2Me CO₂Me

257 258

The reaction of cyclopropane 264 with benzyl isocyanate was carried out using our standard procedure. See General Proceedure D, Experimental Section, Chapter 2.

Isoindolone 265 was obtained in approximately 49% yield, although purification was difficult.

¹

H NMR analysis (300 MHz, CDCl

3

) of showed signals corresponding to the 5- malonyl-containing side chain off the isoindoline ring: δ 3.03–2.94 (m, 1H), 2.83–2.70 (m, 1H), 2.54 (dd, J = 9.9, 7.0, 1H). Further purification was not attempted.

264

FeCl₃ (1.1 equiv) CH₂Cl₂, 23 °C

NC

Bn O

(3 equiv) CO2Me

CO2Me

MeO

MeO OMe

MeO

MeO OMe

N O

Bn CO₂Me MeO2C

265

(1) For selected reviews, see: a) Bentley, K. W. Nat. Prod. Rep. 1992, 9, 365–391; b) Scott, J. D.; Williams, R. M. Chem. Rev. 2002, 102, 1669–1730; c) Pässler, U.;

Knölker, H.-J. The Pyrrolo[2,1-a]isoquinoline Alkaloids. The Alkaloids:

Chemistry and Biology, Elsevier: Place, 2011; Vol. 70, pp 79–151; d) Chrzanowska, M.; Grajewska, A.; Rozwadowska, M. D. Chem. Rev. 2016, 116, 12369–12465.

(2) Ashley, E. R.; Cruz, E. G.; Stoltz, B. M. J. Am. Chem. Soc. 2003, 125, 15000–

15001.

(3) Allan, K. M.; Stoltz, B. M. J. Am. Chem. Soc. 2008, 130, 17270–17271.

(4) a) Trolline: Wang, R. F.; Yang, X. W.; Ma, C. M.; Cai, S. Q.; Li, J. N.; Shoyama, Y. Heterocycles 2004, 63, 1443–1448; b) Olercacein E: Xiang, L., Xing, D. M., Wang, W., Wang, R. F., Ding, Y., and Du, L. J. (2005) Alkaloids from Portulaca oleracea L. Phytochemistry 66, 2595−2601; c) Crispine A: Zhang, Q.; Tu, G.;

Zhao, Y.; Cheng, T. Tetrahedron 2002, 58, 6795–6798.

(5) Rubina, M.; Rubin, M.; Gevorgyan, V. J. Am. Chem. Soc. 2003, 125, 7198–7199.

(6) Rubina, M.; Rubin, M.; Gevorgyan, V. J. Am. Chem. Soc. 2002, 124, 11566–

11567.

(7) Ivanova, O. A.; Budynina, E. M.; Chagarovskiy, A. O.; Trushkov, I. V.;

Melnikov, M. Ya. J. Org. Chem. 2011, 76, 8852–8868.

(8) Complete cleavage of the polarized C–C bond is thought to occur given the rapid racemization of a less-activated analogue (dimethyl 2-phenylcyclopropane-1,1- dicarboxylate) upon exposure to iron(III) chloride. See Chapter 2 for details.

(9) Volkova, Y. A.; Budynina, E. M.; Kaplun, A. E.; Ivanova, O. A.; Chagarovsky, A. O.; Skvortsov, D. A.; Rybakov, V. B.; Trushkov, I. V.; Melnikov, M. Ya.

Chem. Eur. J. 2013, 19, 6586–6590.

(10) Rakhmankulov, E. R.; Ivanov, K. L.; Budynina, E. M.; Ivanova, O. A.;

Chagarovskiy, A. O.; Skvortsov, D. A.; Latyshev, G. V.; Trushkov, I. V.;

Melnikov, M. Ya. Org. Lett. 2015, 17, 770–773.

(11) Ivanova, O. A.; Budynina, E. M.; Chagarovskiy, A. O.; Rakhmankulov, E. R.;

Trushkov, I. V.; Semeykin, A. V.; Shimanovskii, N. L.; Melnikov, M. Ya. Chem.

Eur. J. 2011, 17, 11738–11742.

(12) Sandridge, M. J.; France, S. Org. Lett. 2016, 18, 4218–4221.

(13) For selected examples, see: a) Zhang, G.; Sun, S.; Zhu, T.; Lin, Z.; Gu, J.; Li, D.;

Gu, Q. Phytochemistry 2011, 72, 1436–1442; b) Lü, W.-W.; Gao, Y.-J.; Su, M.-

Z.; Luo, Z.; Zhang, W.; Shi, G.-B. Helv. Chim. Acta 2013, 96, 109–133; c) Zheng, C.-J.; Shao, C.-L.; Wu, L.-Y.; Chen, M.; Wang, K.-L.; Zhao, D.-L.; Sun, X.-P.;

Chen, G.-Y.; Wang, C.-Y. Mar. Drugs 2013, 11, 2054–2068.

(14) These cyclopropanes are not known in the literature. It is possible the combination of such strong donor and acceptor groups causes significant instability, preventing their isolation.

(15) Shi, M.; Shen, Y. Helv. Chim. Acta 2002, 85, 1355–1363.

(16) Pangborn, A. B.; Giardello, M. A.; Grubbs, R. H.; Rosen, R. K.; Timmers, F. J.

Organometallics 1996, 15, 1518–1520.

(17) Baum, J. S.; Shook, D. A.; Davies, H. M. L.; Smith, D. Synth. Commun. 1987, 17, 1709–1716.

(18) Lebel, H.; Ladjel, C.; Bréthous, L. J. Am. Chem. Soc. 2007, 129, 13321–13326.

(19) Takeda, K.; Akiyama, A.; Nakamura, H.; Takizawa, S.; Mizuno, Y.; Takayanagi, H.; Harigaya, Y. Synthesis 1994, 1063–1066.

(20) Müller, P.; Fernandez, D. Helv. Chim. Acta 1995, 78, 947–958.

(21) Skvorcova, M.; Grigorjeva, L.; Jirgensons, A. Org. Lett. 2015, 17, 2902–2904.

APPENDIX 3

Spectra Relevant to Chapter 2:

Lewis Acid Mediated (3 + 2) Cycloadditions of

Donor–Acceptor Cyclopropanes with Heterocumulenes

Figure A3.11 H NMR (500 MHz, CDCl3) of compound 195.

195

CO2Me

CO2Me Cl

Figure A3.3 ¹³C NMR (126 MHz, CDCl3) of compound 195.

Figure A3.2 Infrared spectrum (thin film/NaCl) of compound 195.

Figure A3.41 H NMR (500 MHz, CDCl3) of compound 197.

197

CO2Me

CO2Me Me

Me Me

Figure A3.6 ¹³C NMR (126 MHz, CDCl₃) of compound 197.

Figure A3.5 Infrared spectrum (thin film/NaCl) of compound 197.

Figure A3.71 H NMR (500 MHz, CDCl3) of compound 144.

N

O CO2Me

i-Pr CO2Me 144

Figure A3.9 ¹³C NMR (126 MHz, CDCl₃) of compound 144.

Figure A3.8 Infrared spectrum (thin film/NaCl) of compound 144.

Figure A3.101 H NMR (500 MHz, CDCl3) of compound 145.

N

O CO2Me

CO2Me 145MeO

Bn

Figure A3.11 Infrared spectrum (thin film/NaCl) of compound 145.

Figure A3.12 ¹³C NMR (126 MHz, CDCl₃) of compound 145.

Figure A3.131 H NMR (500 MHz, CDCl3) of compound 146.

N

O CO2Me

CO2MeBn 146Cl

Figure A3.15 ¹³C NMR (126 MHz, CDCl₃) of compound 146.

Figure A3.14 Infrared spectrum (thin film/NaCl) of compound 146.

Figure A3.161 H NMR (500 MHz, CDCl3) of compound 147.

N

O CO2Me

CO2Me 147

Figure A3.18. ¹³C NMR (126 MHz, CDCl₃) of compound 147.

Figure A3.17 Infrared spectrum (thin film/NaCl) of compound 147.

Figure A3.191 H NMR (500 MHz, CDCl3) of compound 148.

n-Bu N

O CO2Me

CO2Me 148

Figure A3.21 ¹³C NMR (126 MHz, CDCl₃) of compound 148.

Figure A3.20 Infrared spectrum (thin film/NaCl) of compound 148.

Figure A3.221 H NMR (500 MHz, CDCl3) of compound 149.

N

O CO2Me

CO2Me 149

H

Figure A3.24 ¹³C NMR (126 MHz, CDCl₃) of compound 149.

Figure A3.23 Infrared spectrum (thin film/NaCl) of compound 149.

Figure A3.251 H NMR (500 MHz, CDCl3) of compound 158.

S

N CO2Me CO2Me 158

Figure A3.27 ¹³C NMR (126 MHz, CDCl₃) of compound 158.

Figure A3.26 Infrared spectrum (thin film/NaCl) of compound 158.

Figure A3.281 H NMR (500 MHz, CDCl3) of compound 158.

MeO

S

N CO2Me CO2Me 150

Figure A3.30 ¹³C NMR (126 MHz, CDCl₃) of compound 150.

Figure A3.29 Infrared spectrum (thin film/NaCl) of compound 150.

Figure A3.311 H NMR (500 MHz, CDCl3) of compound 159.

Ph

S

N CO2Me CO2Me 159

Figure A3.33 ¹³C NMR (126 MHz, CDCl₃) of compound 159.

Figure A3.32 Infrared spectrum (thin film/NaCl) of compound 159.

Figure A3.341 H NMR (500 MHz, CDCl3) of compound 160.

S

N CO2Me CO2Me Cl 160

Figure A3.36 ¹³C NMR (126 MHz, CDCl₃) of compound 160.

Figure A3.35 Infrared spectrum (thin film/NaCl) of compound 160.

Figure A3.371 H NMR (500 MHz, CDCl3) of compound 161.

Me

S

N CO2Me CO2Me 161

Figure A3.39 ¹³C NMR (126 MHz, CDCl₃) of compound 161.

Figure A3.38 Infrared spectrum (thin film/NaCl) of compound 161.

Figure A3.401 H NMR (500 MHz, CDCl3) of compound 162.

t-Bu

S

N CO2Me CO2Me 162

Figure A3.42 ¹³C NMR (126 MHz, CDCl₃) of compound 162.

Figure A3.41 Infrared spectrum (thin film/NaCl) of compound 162.

Figure A3.431 H NMR (500 MHz, CDCl3) of compound 163.

O

S

N CO2Me CO2Me 163

O

Me

Figure A3.45 ¹³C NMR (126 MHz, CDCl₃) of compound 163.

Figure A3.44 Infrared spectrum (thin film/NaCl) of compound 163.

Figure A3.461 H NMR (500 MHz, CDCl3) of compound 155.

Me

S

N CO2Me CO2Me

Me Me 155

Figure A3.48 ¹³C NMR (126 MHz, CDCl₃) of compound 155.

Figure A3.47 Infrared spectrum (thin film/NaCl) of compound 155.