The endocyclic restriction test: The geometries of nucleophilic substitutions at sulfur(VI) and sulfur(II)

Article abstract of DOI:10.1021/jo8016428

(Chemical Equation Presented) The trajectories for nucleophilic substitutions at sulfur(VI) and sulfur(II) have been investigated by the endocyclic restriction test. On the basis of double-labeling experiments, the sulfur(VI) transfer in the conversion of 1 to 2 is found to be intramolecular, while the sulfur(VI) transfer in the conversion of 3 to 4 and the sulfur(II) transfer in the conversion of 5 to 6 are found to be intermolecular. These results are taken to be consistent with transition structures for these sulfur transfer reactions which require a large angle between the entering and leaving group, a geometry analogous to apical group positions in trigonal bipyramidal transition states.

Full text of DOI:10.1021/jo8016428

The Endocyclic Restriction Test: The Geometries of Nucleophilic
Substitutions at Sulfur(VI) and Sulfur(II)†
Stephen G. Jarboe, Michael S. Terrazas, and Peter Beak*
Department of Chemistry, UniVersity of Illinois, Roger Adams Laboratory, 600 South Mathews AVenue,
Urbana, Illinois 61801
beak@scs.uiuc.edu
ReceiVed July 31, 2008
The trajectories for nucleophilic substitutions at sulfur(VI) and sulfur(II) have been investigated by the
endocyclic restriction test. On the basis of double-labeling experiments, the sulfur(VI) transfer in the
conversion of 1 to 2 is found to be intramolecular, while the sulfur(VI) transfer in the conversion of 3
to 4 and the sulfur(II) transfer in the conversion of 5 to 6 are found to be intermolecular. These results
are taken to be consistent with transition structures for these sulfur transfer reactions which require a
large angle between the entering and leaving group, a geometry analogous to apical group positions in
trigonal bipyramidal transition states.
Introduction
membered endocyclic rings, which would not allow the
simultaneous apical entering and leaving groups of trigonal
bipyramidal transition structures. However, a similar sulfonyl
transfer was found not to occur in a six-membered endocyclic
ring. Both addition-elimination and large angle transition
structures have been reported for sulfenyl (S(II)) substitutions.8
We now report applications of the endocyclic restriction test
to evaluate the geometries of nucleophilic substitutions at
Substitutions at sulfur are of interest in chemistry and
biology.1 The limiting pathways which describe the mechanistic
possibilities of initial ionization, concerted displacement, or
addition-elimination differ in the timing of bond making and
bond breaking, the number of elementary steps, and the possible
geometries of the transition structures.
Previous investigations of nucleophilic substitutions at sul-
fur(VI) and sulfur(II) have supported different pathways. These
mechanisms include sulfenium and sulfonium cationic intermedia-
tes2,3 as well as trigonal bipyramidal sulfuranes as intermediates
or transition structures.4-6,7e The generally invertive course for
sulfur(VI) substitutions is consistent with the latter, although
competing retentive reactions have also been noted. Sulfonyl
(S(VI)) transfers have been observed within four- and five-
(5) For examples of linear free energy studies of sulfur substitution, see: (a)
Wilson, J. M.; Bayer, R. J.; Hupe, D. J. J. Am. Chem. Soc. 1977, 99, 7922–
7926. (b) Ciuffarin, E.; Fava, A. Prog. Phys. Org. Chem. 1968, 6, 81–109. (c)
Biasotti, J. B.; Andersen, K. K. J. Am. Chem. Soc. 1971, 93, 1178–1182. (d)
Choi, J. H.; Lee, B. C.; Lee, H. W.; Lee, I. J. Org. Chem. 2002, 67, 1277–1281.
(e) Baxter, N. J.; Rigoreau, L. J. M.; Laws, A. P.; Page, M. I. J. Am. Chem. Soc.
2000, 122, 3375–3385. (f) Andersen, K. K.; Bray, D. D.; Chumpradit, S.; Clark,
M. E.; Habgood, G. J.; Hubbard, C. D.; Young, K. M. J. Org. Chem. 1991, 56,
6508–6516.
(6) For examples of calculations of sulfur substitutions, see: (a) Bachrach,
S. M.; Hayes, J. M.; Dao, T.; Mynar, J. L. Theor. Chem. Acc. 2002, 107, 266–
271. (b) Lee, I.; Kim, C. K.; Li, H. G.; Sohn, C. K.; Kim, C. K.; Lee, H. W.;
Lee, B.-S. J. Am. Chem. Soc. 2000, 122, 11162–11172. (c) Bachrach, S. M.;
Mulhearn, D. C. J. Phys. Chem. 1996, 100, 3535–3540. (d) Cameron, D. R.;
Thatcher, R. J. J. Org. Chem. 1996, 61, 5986–5997. (e) Bachrach, S. M.; Woody,
J. J.; Mulhearn, D. C. J. Org. Chem. 2002, 67, 8983.
(7) (a) Johnson, C. R.; Jonsson, E. U.; Wambsgans, A. J. Org. Chem. 1979,
44, 2061–2065. (b) Mikolajczyk, M.; Drabowicz, J. Top. Stereochem. 1992, 13,
333. (c) Wudl, F.; Lee, T. B. K. J. Am. Chem. Soc. 1973, 95, 6349–6358. (d)
Oae, S.; Yokoyama, M.; Furakawa, N. Tetrahedron Lett. 1968, 38, 4131–4134.
(e) Andersen, K. K.; Chumpradit, S.; McIntyre, D. J. J. Org. Chem. 1988, 53,
4667–4675. (f) Hellwinkel, D.; Supp, M. Chem. Ber. 1976, 51, 1525–1529. (g)
Baxter, N. J.; Laws, A. P.; Rigoreau, L.; Page, M. Chem. Commun. 1997, 2037,
2038.
† Dedicated to the memory of Professor Albert I. Meyers, an outstanding
scientist, a generous colleague, and a wonderful friend.
(1) (a) Cremlyn, R. An Introduction to Organosulfur Chemistry; John Wiley
& Sons: New York, 1996. (b) PerspectiVes in the Organic Chemistry of Sulfur;
Elsevier: New York, 1987. (c) Organic Sulfur Chemistry; Elsevier: New York,
1985.
(2) (a) Do, Q. T.; Elothmani, D.; Guillanton, G. L. Tetrahedron Lett. 1998,
39, 4657–4658. (b) Kobayashi, K.; Sato, S.; Horn, E.; Furukawa, N. Tetrahedron
Lett. 1998, 39, 2593–2596.
(3) (a) Cox, R. A. J. Chem. Soc., Perkin Trans. 2 1997, 1743. (b) Kutuk, H.;
Bekdemir, Y.; Soydas, Y. J. Phys. Org. Chem. 2001, 14, 224–228.
(4) (a) Bunton, C. A.; Hendy, B. N. J. Chem. Soc. 1962, 2562. (b) Kaiser,
E. T. Acc. Chem. Res. 1970, 3, 145–151. (c) Oae, S.; Fukumoto, R.; Kiritani, R.
Bull. Chem. Soc. 1963, 36, 346–348.
10.1021/jo8016428 CCC: $40.75
Published on Web 11/16/2008
2008 American Chemical Society
J. Org. Chem. 2008, 73, 9627–9632 9627

Jarboe et al.
SCHEME 1
as shown. From 15, Boc protection to 16 followed by carbamate
methylation provided 17. Reduction of the nitro group to give
the amine 18 was followed by a two-step protocol for the bis-
sulfonylation to afford 19 and subsequently 20. Deprotection
of the carbamate completed the synthesis of 7.
The synthesis of sulfonamide 8 (Scheme 4) was accomplished
in 37% yield over five steps from 21. The amine-borane
complex 22 was converted to the benzyl amine 23. Protection
as the tert-butyl carbamate, followed by installation of both
sulfonyl groups, provided 25 via 24. Removal of the carbamate
completed the synthesis of 8.
Intermediate 19 was used for the independent synthesis of 9
via 26 as shown in Scheme 5.
Direct sulfonylation of 23 with benzenesulfonyl chloride
provided 10 (Scheme 6) in 46% yield, along with mono- and
trisulfonylated products.
Transfer of Sulfonyl Sulfur(VI): Conversions of 7 to 9
and 8 to 10. The sulfonyl transfers were carried out by
deprotonations with lithium tetramethylpiperidine (LiTMP).
From 7 and 8, 9 and 10 could be isolated in 19% and 29%
yields, respectively (Scheme 7). These reactions proceed via
the conversions of 1 to 2 and 3 to 4, respectively.
SCHEME 2
Synthesis of Labeled Sulfonamides 9 and 10. Isotopically
substituted 7 and 8 required for double-label crossover experi-
ments were prepared by the reactions used for the unlabeled
compounds using deuterium labeled benzene sulfonyl chloride.
For the synthesis of labeled 7-d10, benzene-d6 (99.6%
isotopically enriched) was allowed to react with deuterosulfuric
acid followed by treatment with thionyl chloride to give 27-d5
(Scheme 8).
sulfur(VI) and sulfur(II). In this approach, linking a nucleophile
to a sulfur bearing a leaving group through a tether places a
restrain in the geometry of a possible intramolecular transfer.
A short tether would not allow simultaneous disposition of an
apical nucleophile and leaving group within an endocyclic ring,
and the reaction would be expected to proceed intermolecularly.
A long tether, however, would make such a transition structure
accessible, and intramolecular transfer could become the reaction
pathway.9 An initial dissociative pathway would have a mo-
lecularity which would be independent of tether length. The
sulfur transfers we have investigated are 1 to 2 and 3 to 4 for
sulfur(VI) and 5 to 6 for sulfur(II) (Scheme 1).
Sulfonylation of 18 with 27-d5 gave 19-d5. Deprotonation with
NaH and reaction with 27-d5 provided 20-d10. Standard Boc
deprotection completed the synthesis of 7-d10 (Scheme 9).
For the synthesis of 8-d10, the direct chlorosulfonation of
benzene d6 was used to prepare 27-d5 which was used in the
standard sulfonylation of 24 to give labeled 25-d10 (Scheme 10).
Deprotection of 20-d10 gave deuterium-labeled 7-d10. Although
mass spectral analysis showed that deuterium incorporation was
incomplete, presumably due to extensive exchange of deuterium
for protium in the initial reaction, 7-d10 was sufficiently labeled
to give a definitive result in the double-labeling experiment.
Double-Labeled Crossover Experiments: Endocyclic
Restriction Tests with 7 and 8. The molecularities for the
conversions of 7 to 9 and 8 to 10 were determined by double-
labeling crossover experiments. Shown in Scheme 11 are the
possibilities for a mixture of unlabeled and fully labeled
compounds. If the phenylsulfonyl transfer is intramolecular,
there will be no crossover of label, and the products will have
the same double-labeled and unlabeled distribution as the starting
mixture. If the phenylsulfonyl transfer is intermolecular, there
will be crossover, and the products will be doubly, singly and
unlabeled in a statistical ratio relative to the starting mixture.
A double-labeled crossover experiment was performed with
7 and 7-d10 to test the molecularity of phenylsulfonyl transfer
with the long-tethered substrate, and these results are presented
in Table 1. Treatment of an equimolar mixture of 7 and 7-d10
with LiTMP at 0.1 and 0.01 M followed by isolation of 9 and
analysis of isotopic composition by FABMS gave the results
shown in Table 1. Table 1 also shows the results expected for
intramolecular and intermolecular phenylsulfonyl transfer.
The data show that when the crossover reaction was carried
out at a concentration of 0.1 M, the transfer of the sulfonyl
Results and Discussion
Endocyclic Restriction Test at Sulfur(VI). The conversions
of the aryl sulfonamides 7 and 8 to alkyl sulfonamides 9 and
10 (Scheme 2) via 1 to 2 and 3 to 4 involve sulfur(VI) transfers
which could occur within a 17-membered or 6-membered
endocyclic ring, respectively. The molecularity of these reactions
has been investigated by double labeling experiments.
Syntheses of Sulfonamides 7-10. The long tethered sub-
strate 7 was prepared in 10 steps (Scheme 3). The conversion
of 11 to 15 via 12 to 13, and 14 followed standard procedures
(8) (a) Hogg, D. R.; Vipond, P. W. J. Chem. Soc. C 1970, 2142–2144. (b)
Rosenfield, R. C., Jr.; Parthasarathy, R.; Dunitz, J. D J. Am. Chem. Soc. 1977,
4860. (c) Singh, R.; Whitesides, G. M. J. Am. Chem. Soc. 1990, 112, 6340. (d)
Luczak, L.; Lopusinski, A.; Michalski, J. Tetrahedron 1998, 54, 9731. (e) Fachini,
M.; Lucchini, V.; Modena, G.; Pasi, M.; Pasquato, L. J. Am. Chem. Soc. 1999,
121, 3944–3950.
(9) Lee, S. J.; Terrazas, M. S.; Pippel, D. J. J. Am. Chem. Soc. 2003, 125,
7307, and references cited therein for other cases using the endocyclic restriction
test. The data from double-labeling experiments provide definitive distinctions
between intermolecular and intramolecular pathways for these sulfur transfers.
Assignments for the favored geometries for atom-transfer reactions under this
test are conclusive and independent of yields. Low yields of the atom-transferred
products or the operation of pathways which give other products do not
compromise the test under this protocol.
9628 J. Org. Chem. Vol. 73, No. 24, 2008

Endocyclic Restriction Test
SCHEME 3
SCHEME 4
SCHEME 5
SCHEME 6
SCHEME 7
group occurs by both an intramolecular and intermolecular
pathway. At the dilution of 0.01 M, however, the product
distribution changes to reveal a significant increase in intramo-
lecular substitution. This increase on dilution is consistent with
a first-order intramolecular reaction which becomes competitive
with a second-order intermolecular reaction at the higher
concentration.
A double-labeled crossover experiment with the short-tethered
substrate was carried out by treatment of a 0.01 M mixture of
8 and 8-dn with LiTMP. The isotopic distributions of 8 and 10
as determined by FABMS, along with those expected for a
completely intramolecular and intermolecular transfer, are shown
in Table 2.10 The incomplete labeling of 8-dn leads to a wide
distribution of label, but the results are definitive.
The results in Tables 1 and 2 show that under the same
conditions the conversion of 7 to 9 via 1 to 2 can be an
intramolecular reaction, whereas the conversion of 8 to 10 via
3 to 4 is intermolecular.
J. Org. Chem. Vol. 73, No. 24, 2008 9629

Jarboe et al.
SCHEME 8
SCHEME 9
SCHEME 11
TABLE 1. Isotopic Ratios for the Double-Labeled Endocyclic
Restriction Test Conversion of 7 to 9 at 0.01 M
7-dn
9-dn
Experimental
theoretical
dn
0.1 M
33
2
32
3
0.01 M
48
intramolecular
intermolecular
d0
d4
d5
d9
d10
50
0
0
2
48
50
0
0
2
48
25
1
49
1
1
7
2
SCHEME 10
30
42
24
TABLE 2. Isotopic Ratios for the Double-Labeled Endocyclic
Restriction Test Conversion of 8 to 10 at 0.01 M
8-dn
10-dn
experimental
theoretical
dn
0.01 M
intramolecular
intermolecular
d0
d1
d2
d3
d4
d5
d6
d7
d8
d9
d10
43
1
1
3
5
7
9
10
10
7
24
4
7
10
14
15
6
6
6
5
3
43
1
1
3
5
7
9
10
10
7
22
5
8
11
15
17
5
6
5
4
2
4
4
SCHEME 12
The results rule out mechanisms that do not require an almost
linear arrangement of the entering and leaving nitrogen about
sulfur in these phenylsulfonyl transfers. That the putative
transition state is reasonably a trigonal bipyramidal structure
in which a large bond angle between the entering and leaving
groups is required for product formation is consistent with
7
previous experimental work.
Synthesis of Sulfenamides 28 and 29. The synthesis of 28
was completed in five linear steps in 63% overall yield. Borane
reduction of commercially available o-bromobenzyl nitrile (30)
provided amine 31, which was converted to the N-Boc carbam-
ate 32. Deprotonation and alkylation afforded the secondary
carbamate 33. The secondary amine 34, obtained with 10%
trifluoroacetic acid, allowed installation of the phenylsulfenyl
group with S-phenylthiophthalimide to provide 28 (Scheme 13).
From commercially available 35, the synthesis of 29 was
completed in five steps (Scheme 14) in 91% yield (Scheme 14).
Borane reduction of the nitrile 35 and subsequent carbamate
protection gave 37 via 36. Standard alkylation using NaH and
Endocyclic Restriction Test at Sulfur(II). The conversion
of the sulfenamine 28 to sulfide 29 (Scheme 12) via 5 to 6
involves a transfer of sulfur(II) which could occur within a
6-membered endocyclic ring. The molecularity of this substitu-
tion has been investigated by a double-labeled crossover
experiment with 28 and 28-d8.
(10) In earlier runs, 8-dn had tended to rearrange prior to mixing with 8.
Careful purification of each component and analysis was carried out to show
this did not occur prior to the reaction. The fact that there was not scrambling
of the labels in the conversion of 7 to 9 under the same conditions establishes
that label scrambling prior to phenyl sulfonyl transfer is not occurring in this
case.
9630 J. Org. Chem. Vol. 73, No. 24, 2008

Endocyclic Restriction Test
SCHEME 13
SCHEME 17
TABLE 3. Isotopic Ratios for the Endocyclic Restriction Test
Conversion of 28 to 29 at 0.1 M
29
SCHEME 14
experimental
0.1 M 0.01 M
theoretical
dn
28-dn
intramolecular
intermolecular
d0
d3
d5
d8
41
4
4
21
27
23
29
23
25
26
26
41
4
4
20
25
25
31
52
52
SCHEME 18
SCHEME 15
Double-Labeled Crossover Experiments: The Endocyclic
Restriction Test with 28. The reaction of a mixture of 28 and
28-d8 would produce a statistical mixture of unlabeled 29,
29-d3, 29-d5, and 29-d8 from an intermolecular transfer, while
an intramolecular reaction would provide only 29 and 29-d8
with an isotopic ratio the same as that of the reactants.
SCHEME 16
Mixtures of 28, 28-d3, 28-d5, and 28-d8 were submitted to
the reaction conditions at 0.1 and 0.01 M. The isotopic
distributions of 28 and 29 as determined by mass spectral
analysis are shown in Table 3, along with the results expected
for intramolecular and intermolecular transfer (Scheme 18).
Recovery of unreacted starting material showed no isotopic
exchange had occurred to the mixture of 28, 28-d3, 28-d5, and
28-d8.
iodomethane provided 38. The diaryl sulfide functionality was
installed through palladium-catalyzed cross-coupling of 38 with
thiophenol to give 39, which on standard deprotection afforded
29.
The conversion of 5 to 6 as indicated by the compositions
of 28 and 29 show the reaction is intermolecular under these
conditions. These results are consistent with a requirement
of a linear transition state of the entering carbon nucleophile
and the nitrogen leaving group in this sulfur(II) transfer.11
Transfer of Sulfenyl Sulfur(II): Conversions of 28 to
29. Lithium-bromide exchange of 28 with t-BuLi provided the
carbanion nucleophile for sulfenyl group transfer of 5 to give 6
and then 29. Treatment of 28 with 2.0 equiv of t-BuLi in diethyl
ether at -78 °C for 1 h provided 29 in 13% yield (Scheme 15).
Synthesis of Labeled 28. The preparation of 28-d8 was
carried out from bromobenzene-d5 following standard proce-
dures. Labeled phenylmagnesium bromide was treated with
elemental sulfur to provide crude 40-d5, which was allowed to
react with chlorine gas to provide 41-d5. Conversion to 42-d5
was completed by reaction with phthalimide and triethylamine
in DMF (Scheme 16).
(11) Our efforts to investigate a long-chain tether for sulfur(II) by the
investigation of i were not successful (Jarboe, S. Ph.D. Thesis, University of
Illinois, 2002). Absent the experimental results for that case, it could be argued
that there is insufficient dilution in these experiments for a definitive conclusion.
Our preference, consistent with previous work, is to favor a linear transition
structure.8a
Alkylation of 32 with iodomethane-d3 provided 33-d3 with
high deuterium incorporation, as determined by both 1H NMR
and FD-MS analysis. Deprotection to 34-d3 and sulfenylation
using 42-d5 provided 28-d8 (Scheme 17).
(12) Tollefson, M. B.; Beak, P. J. Am. Chem. Soc. 1996, 118, 9052.
J. Org. Chem. Vol. 73, No. 24, 2008 9631

Jarboe et al.
two times with CH2Cl2, and the organics were dried over MgSO4.
The drying agent was removed by filtration and the solvent removed
by distillation under reduced pressure leaving a clear viscous yellow
oil. Purification by silica gel flash chromatography (20% EtOAc/
petroleum ether) provided 9 as a clear colorless oil in 98% yield (0.346
Conclusion
From the present work, the reaction pathways for sulfur(VI)
and sulfur(II) group transfers in nucleophilic substitutions
may be considered to favor a linear transition structure
represented by 30. This classic transition state structure, long
established for SN2 nucleophilic substitutions at sp3-hybrid-
ized carbon, is also consistent with the geometrical require-
ments for substitution at nitrogen, oxygen, bromine, and
chlorine.9 Nucleophilic substitution at phosphorus has been
shown to be able to proceed through an addition-elimination
process in which the geometry of the transition structure is
not always required to be linear.12 Nonetheless, simultaneous
linear orientation of the incoming nucleophile and the leaving
group analogous to trigonal bipyramidal transition structures
for nucleophilic displacements can be considered to be the
favored pathway for transfer of atoms in the upper right-
hand corner of the periodic table.
1
g) for the two steps: H NMR (CDCl3, 500 MHz) δ 1.22-1.36 (m,
15H), 1.49-1.70 (m, 5H), 2.71 (s, 3H), 2.99 (t, J ) 7 Hz, 2H), 3.72
(t, J ) 7 Hz, 2H), 6.70 (d, J ) 8 Hz, 1H), 6.89 (t, J ) 8 Hz, 1H), 6.96
(s, 1H), 7.02 (t, J ) 8 Hz, 1H), 7.38 (t, J ) 8 Hz, 2H), 7.46-7.60 (m,
5H), 7.71 (d, J ) 8 Hz, 2H), 7.78 (d, J ) 8 Hz, 2H); 13C NMR (CDCl3,
125.7 MHz) δ 25.9, 26.4, 27.5, 28.9, 29.1, 29.3, 29.4, 29.4, 34.5, 36.9,
50.1, 68.5, 111.3, 120.8, 121.8, 125.6, 125.7, 127.1, 127.3, 128.7, 129.0,
132.4, 132.8, 137.6, 139.2, 149.1. Anal. Calcd for C29H38N2O5S2: C,
62.91; H, 7.04; N, 4.89. Found: C, 62.59; H, 6.97; N, 4.79.
Endocyclic Restriction Test for Sulfonyl Transfer for 7 and
7-d10. To a solution of 0.149 g (0.260 mmol) of 7 and 0.151 g
(0.260 mmol) of 7-d10 at -78 °C was added 0.38 mL (0.571
mmol) of LiTMP (1.5 M in THF) in 5.2 mL of THF. The dry
ice/acetone bath was removed and the solution stirred as it slowly
warmed to room temperature for 16 h. The yellow mixture was
diluted with 3 mL of brine and extracted three times with Et2O.
The combined organics were dried over MgSO4. The drying
agent was removed by filtration and the solvent removed by
distillation under reduced pressure to give 275 mg of a thick
orange oil. This mixture was purified by silica gel flash
chromatography (30% EtOAc/petroleum ether as eluent) to give
57 mg (19%) of 9.
Endocyclic Restriction Test for Sulfonyl Transfer for 8 and
8-d10. To a solution of 0.040 g (0.281 mmol) of TMP in 5 mL of
THF was added 0.164 mL (0.238 mmol) of n-BuLi (1.45M).
The solution was stirred at room temperature for 10 min and
subsequently cooled to -78 °C. By way of cannula, the LiTMP
solution was transferred to a -78 °C solution of 45 mg (0.108
mmol) of 8 and 48 mg (0.108 mmol) of 8-d10 in 215 mL of
THF (concentration of solution ) 0.01M). The dry ice/acetone
bath was removed and the solution stirred as it slowly warmed
to room temperature for 16 h. The yellow mixture was diluted
with 20 mL of brine and extracted three times with Et2O. The
combined organics were dried over MgSO4. The drying agent
was removed by filtration and the solvent removed by distillation
under reduced pressure to give 69 mg of a thick orange oil. The
crude mixture was flash chromatographed through a silica gel
column (30% EtOAc/petroleum ether as eluent) to give 7 mg of
10 (6%).
Endocyclic Restriction Test for Sulfur Transfer for 28 and
28-d6. To a -78 °C solution consisting of 20.2 mg (0.078 mmol)
of 28 and 20.7 mg (0.078 mmol) of 28-d6 in 1.55 mL (0.1 M)
of Et2O was added 0.193 mL (0.31 mmol) of t-BuLi (1.6 M).
The solution was allowed to react at -78 °C for 1 h prior to
being quenched with 100 µL of MeOH. After being warmed to
room temperature, the mixture was diluted with 5 mL of water
and subsequently extracted three times with Et2O. The combined
organics were dried over MgSO4 and filtered, and the solvent
was removed by distillation under reduced pressure to yield 20.0
mg of a pale yellow oil.
Experimental Section
The compounds synthesized were determined to be >95% pure
by 1H NMR and 13C NMR analysis as well as by elemental analysis
in selected cases. The products of the endocyclic restriction tests
were identified by comparisons of NMR spectra and GC retention
times with the authentic materials described below and in the
Supporting Information. The isotopic compositions were determined
by FI/MS.
N-Methyl-11-(2-(N,N-bisphenylsulfonyl)aminophenoxy)unde-
cylamine (7). To a solution of 0.75 g (1.11 mmol) of 20 in 10 mL
of CH2Cl2 was added 1 mL of trifluoroacetic acid. The solution
immediately turned from clear to an orange color and was allowed to
stir at room temperature for 16 h. The mixture was basified with 10%
NaOH solution, extracted three times with CH2Cl2, and the combined
organics were dried over MgSO4. The drying agent was filtered and
the solvent removed by distillation under reduced pressure leaving 7
1
as a clear yellow oil in 78% yield (0.50 g): H NMR (500 MHz,
CDCl3) δ 1.18-1.34 (m, 16H), 1.47 (m, 2H), 2.07 (br s, 1H), 2.42 (s,
3H), 2.56 (t, J ) 7 Hz, 2H), 3.63 (t, J ) 2H), 6.85 (dd, J ) 8, 1 Hz,
1H), 6.91 (td, J ) 8,1 Hz, 1H), 7.10 (dd, J ) 8, 2 Hz, 1H), 7.37 (ddd,
J ) 8, 7, 2 Hz, 1H), 7.49 (m, 4H), 7.62 (tt, J ) 7, 1 Hz, 2H), 7.96 (m,
4H); 13C NMR (125.7 MHz, CDCl3) δ 25.4, 27.2, 28.5, 29.2, 29.4,
29.4, 29.5, 29.5, 29.6, 36.2, 52.0, 68.2, 112.6, 120.2, 122.7, 128.5,
128.7, 131.9, 133.0, 133.4, 140.3, 157.3.
N-Benzenesulfonyl-N-(2-(N-benzenesulfonyl)aminobenzyl)un-
decylamine (9). To a solution of 0.328 g (0.62 mmol) of 19 in 5 mL
of CH2Cl2 was added 0.5 mL of trifluoroacetic acid. The solution
immediately turned from clear to an orange color and was allowed to
stir at room temperature for 6 h. The mixture was basified with 10%
NaOH solution and extracted three times with CH2Cl2, and the
combined organics were dried over MgSO4. The drying agent was
filtered and the solvent removed by distillation under reduced pressure
leaving 26 as a white solid that was resuspended in 5 mL of CH2Cl2.
To this solution was added 0.097 g (1.23 mmol) of pyridine and 0.114
g (0.65 mmol) of benzenesulfonyl chloride, and the solution was stirred
at room temperature for 24 h. The solution was washed twice with
10% aqueous HCl. The combined aqueous portions were extracted
Acknowledgment. We are grateful for support by the
National Institutes of Health (GM-18874), the National
Science Foundation (9819432), and the James R. Eiszner
Chair in Chemistry.
Supporting Information Available: Experimental proce-
dures and spectroscopic data for new compounds are provided.
This material is available free of charge via the Internet at
http://pubs.acs.org.
JO8016428
9632 J. Org. Chem. Vol. 73, No. 24, 2008