The Journal of Organic Chemistry
Note
(m, 2H), 4.72−4.68 (m, 2H), 4.42−4.12 (m, 4 H), 3.76−3.64/3.63−
3.51 (m, 2 H), 3.25/3.13 (m, 2H), 2.26/2.23 (s, 3 H), 2.14/2.04 (s, 3
H, 2.07/1.03); 13C NMR (CDCl3) δ 169.1, 168.6, 147.0, 146.8, 145.5,
145.2, 141.1, 140.9, 137.4, 137.2, 136.3, 135.9, 133.6, 133.5, 133.2,
132.0, 131.8, 128.3, 128.1, 127.8, 127.5, 127.2, 125.1, 124.9, 124.6,
124.5, 82.0, 81.0, 80.3, 79.3, 75.1, 67.3, 66.9, 63.8, 63.6, 63.4, 63.2,
59.1, 58.9, 58.5, 25.0, 20.9, 14.3; HRMS (ES/TOF) m/z [M + H]+
calcd for C26H26FN2O2 417.1978, found 417.1974.
ASSOCIATED CONTENT
* Supporting Information
■
S
1H and 13C NMR spectra for all newly reported compounds,
error analysis, NMR spectroscopy experiments, computational
details, and X-ray data for 1−4, 6−8, and 8a (CIF). The
Supporting Information is available free of charge on the ACS
2,2-Difluoroethyl 3-methyl-2-((11R)-8-methyl-6,12-dihydro-5,11-
methanodibenzo[b,f ][1,5]diazocin-2-yl)benzoate (4): yellow oil;
yield 83 mg (50%); 1H NMR (CDCl3) δ 7.65−7.61 (m, 1 H),
7.40−7.28 (m, 2 H), 7.16−6.69 (m, 4 H), 6.76−6.67 (m, 2 H), 5.65−
5.37 (tt, 1 H), 4.71−4.66 (m, 2 H), 4.38−4.11 (4 H), 3.72−3.61/
3.55−3.44 (m, 2H, 0.76/0.66), 2.25/2.20 (s, 3 H), 2.12/2.03 (s, 3 H,
1.82/0.91); 13C NMR (CDCl3) δ 171.3, 168.2, 167.8, 147.0, 145.7,
145.0, 141.2, 137.5, 136.1, 134.1, 133.7, 131.0, 127.9, 127.7, 127.3,
125.2, 124.6, 114.7, 112.3, 109.9, 75.0, 67.4, 67.2, 66.9, 62.9, 62.7, 62.4,
62.1, 60.5, 59.3, 59.0, 58.5, 25.0, 20.9, 14.3; HRMS (ES/TOF) m/z
[M + H]+ calcd for C26H25F2N2O2 435.1884, found 435.1882.
2,2,2-Trifluoroethyl 3-methyl-2-((11R)-8-methyl-6,12-dihydro-
5,11-methanodibenzo[b,f ][1,5]diazocin-2-yl)benzoate (5): yellow
AUTHOR INFORMATION
Corresponding Author
■
Notes
∥(M.F., T.G., R.S., A.S.) Undergraduate student at Allegheny
College.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The research was supported by an award from Research
Corporation for Scientific Advancement, The Thomas Lord
Charitable Trust Fellowship, and Allegheny College. The X-ray
diffractometer was funded by NSF Grant Nos. 0087210 and
1337296, Ohio Board of Regents Grant No. CAP-491, and by
Youngstown State University. We are grateful for helpful
discussions with Dr. Brijesh Bhayana (Massachusetts General
Hospital), S. Shaun Murphree (Allegheny College), and Agusti
1
oil; yield 64 mg (37%); H NMR (CDCl3) δ 7.66−7.64/7.58−7.56
(d, J = 8 Hz, 1H), 7.39−6.63 (m, 8 H), 4.68−4.64 (m, 2H), 4.37−4.07
(m, 4 H), 3.92−3.82/3.45−3.36 (m, 2 H), 2.24/2.18 (s, 3 H), 2.13/
2.01 (s, 3 H, 3.18/2.15); 13C NMR (CDCl3) δ 171.3, 167.6, 167.0,
147.4, 147.2, 145.8, 145.2, 141.8, 141.4, 137.9, 137.6, 135.6, 135.4,
134.0, 133.8, 133.56, 130.8, 130.2, 128.3, 127.5, 127.3, 127.0, 125.2,
124.7, 67.4, 66.9, 60.6, 60.3, 60.0, 59.6, 59.2, 59.0, 58.6, 21.0, 20.8,
14.4; HRMS (ES/TOF) m/z [M + H]+ calcd for C26H24F3N2O2
453.1790, found 453.1792.
́
́
́
Lledo-Ponsati (University of Girona) and insight provided by
Dr. Allen D. Hunter (Youngstown State University).
1,3-Difluoropropan-2-yl 3-methyl-2-((11R)-8-methyl-6,12-dihy-
dro-5,11-ethanodibenzo[b,f ][1,5]diazocin-2-yl)benzoate (7): yellow
1
oil; yield 100 mg (59%); H NMR (CDCl3) δ 7.64−7.62/7.17−7.15
REFERENCES
■
(d, J = 8 Hz, 1 H), 7.40−7.27 (m, 3 H), 7.07−6.94 (m, 3 H), 6.78−
6.70 (m, 2 H), 5.18−5.05/4.87−4.75 (tp, J = 20, 4.0 Hz, 1 H), 4.39−
4.11 (m, 4 H), 3.70−3.32 (m, 4 H), 2.26/2.22 (s, 3 H), 2.10/2.04 (s, 3
H, 9.22/3.93); 13C NMR (CDCl3): δ 168.2, 147.2, 146.9, 145.4, 145.1,
141.1, 137.6, 136.4, 134.0, 133.6, 131.6, 131.3, 127.4, 125.2, 124.9,
124.7, 81.0, 80.2, 78.5, 70.1, 70.1, 69.9, 67.4, 67.0, 59.3, 59.0, 58.5,
20.9; HRMS (ES/TOF) m/z [M + H]+ calcd for C27H27F2N2O2
449.2041, found 449.2041.
(1) Scholfield, M. R.; Zanden, C. M. V.; Carter, M.; Ho, S. Protein Sci.
2013, 22, 139−152.
(2) Johnson, E. R.; Keinan, S.; Mori-Sanchez, P.; Contreras-Garcia, J.;
Cohen, A. J.; Yang, W. J. Am. Chem. Soc. 2010, 132, 6498−6506.
(3) (a) Umezawa, Y.; Tsuboyama, S.; Takahashi, H.; Uzawa, J.;
Nishio, M. Tetrahedron 1999, 55, 10047−10056. (b) Bazzicalupi, C.;
Dapporto, P. Struct. Chem. 2004, 15, 259−268. (c) Singh, N. J.; Min, S.
K.; Kim, D. Y.; Kim, K. S. J. Chem. Theory Comput. 2009, 5, 515−529.
(d) Vacas, T.; Corzana, F.; Jimenez-Oses, G.; Gonzalez, C.; Gomez, A.
M.; Bastida, A.; Revuelta, J.; Asensio, J. L. J. Am. Chem. Soc. 2010, 132,
12074−12090. (e) Ozawa, T.; Okazaki, K.; Kitaura, K. J. Comput.
Chem. 2011, 32, 2774−2782. (f) Asensio, J. L.; Arda, A.; Canada, F. J.;
Jimenez, -Barbero Acc. Chem. Res. 2013, 46, 946−954.
1,3-Hexafluoropropan-2-yl 3-methyl-2-((11R)-8-methyl-6,12-di-
hydro-5,11-methanodibenzo[b,f ][1,5]diazocin-2-yl)benzoate (8):
yellow oil; yield 73 mg (34%); 1H NMR (CDCl3) δ 7.73−7.71/
7.67−7.65 (d, J = 8.0 Hz, 1 H), 7.47−6.66 (m, 8 H), 5.76/5.50 (sept, J
= 8.0 Hz, 1 H), 4.73−4.64 (m, 2 H), 4.39−4.07 (m, 4 H), 2.26/2.22
(s, 3 H), 2.08/2.04 (s, 3 H, 0.94/0.79); 13C NMR (CDCl3) δ 183.4,
165.8, 165.0, 147.9, 147.4, 145.1, 144.7, 142.3, 141.7, 138.4, 138.3,
135.1, 134.9, 133.9, 133.8, 133.67, 128.6, 128.4, 128.4, 128.3, 128.0,
127.9, 127.8, 127.7, 127.4, 127.4, 127.3, 127.1, 125.1, 124.9, 124.2,
67.0, 58.7, 21.0, 20.9, 20.8; HRMS (ES/TOF) m/z [M + H]+ calcd for
C27H23F6N2O2 521.1664, found 521.1658.
(4) (a) Nishio, M.; Hirota, M. Tetrahedron 1989, 45, 7201.
(b) Nishio, M.; Umezawa, Y.; Hirota, M.; Takeuchi, Y. Tetrahedron
1995, 51, 8665. (c) Tewari, A. K.; Dubey, R. Bioorg. Med. Chem. 2008,
16, 126. (d) Nishio, M.; Umezawa, Y.; Honda, K.; Tsuboyama, S.;
Suezawa, H. CrystEngComm 2009, 11, 1757. (e) Takahashi, O.;
Kohno, Y.; Nishio, M. Chem. Rev. 2010, 110, 6049. (f) Nishio, M. Phys.
Chem. Chem. Phys. 2011, 13, 13873. (g) Zhang, Z. B.; Xia, B. Y.; Han,
C. Y.; Yu, Y. H.; Huang, F. H. Org. Lett. 2010, 12, 3285. (h) Zhang, Z.
B.; Yu, G. C.; Han, C. Y.; Liu, J. Y.; Ding, X.; Yu, Y. H.; Huang, F. H.
Org. Lett. 2011, 13, 4818. (i) Xue, M.; Yang, Y.; Chi, X. D.; Zhang, Z.
B.; Huang, F. H. Acc. Chem. Res. 2012, 45, 1294.
(5) (a) Chopra, D. Cryst. Growth Des. 2012, 12, 541−546. (b) Walker,
M. C.; Thuronyi, B. W.; Charkoudian, L. K.; Lowry, B.; Khosla, C.;
Chang, M. C. Y. Science 2013, 341, 1089−1094.
(6) Jackel, C.; Koksch, B. Eur. J. Org. Chem. 2005, 2005, 4483−4503.
(7) Jackel, C.; Salwiczek, M.; Koksch, B. Angew. Chem., Int. Ed. 2006,
45, 4198−4203.
Model Procedure for Quantification of Folded/Unfolded
Conformers in Solution. The ratio of folded to unfolded
conformation for each balance was determined by the integration of
1
both the top methyl singlets in the H NMR spectra. Due to the
anisotropic effect, the furthest upfield peak represents the unfolded top
methyl hydrogens. This is paired with the next closest upfield peak
(based on integration and temperature dependent NMR analysis). The
methyl peaks for the folded and unfolded conformations can be used
to determine the Gibbs free energy using the equation ΔG°folded
=
−RT ln(Kfolded) = −RT ln(folded/unfolded). The ratio of folded to
unfolded conformation for balance 8 was confirmed by 19F NMR in
CDCl3, CD2Cl2, DMSO-d6, and C6D6. The folded conformation
shows two signals for the chemically inequivalent −CF3 groups and
one signal representing both −CF3 groups for the unfolded
conformation. All NMR spectra have corrected baselines and were
fitted to a Gaussian (line fitting/deconvolution) function using
MNova 8 NMR software.
(8) (a) Nakagawa, Y.; Irie, K.; Yanagita, R. C.; Ohigashi, H.; Tsuda,
K. J. Am. Chem. Soc. 2005, 127, 5746−5747. (b) Leimbacher, M.;
Zhang, Y.; Mannocci, L.; Stravs, M.; Geppert, T.; Scheuermann, J.;
Schneider, G.; Neri, D. Chem. - Eur. J. 2012, 18, 7729−7737.
(9) For articles discussing crystal data in the Cambridge Structural
Databank and the Protein Data Bank for F in close proximity to π
E
J. Org. Chem. XXXX, XXX, XXX−XXX