An alkoxide anion-triggered tert-butyloxycarbonyl group migration. Mechanism and application

Article abstract of DOI:10.1016/j.tetlet.2010.03.009

We report a fast N→O tert-butyloxycarbonyl (Boc) migration of the imide (3R,4R)-tert-butyl 3-((6-(bis(tert-butoxycarbonyl)amino)-4-methylpyridin-2-yl)methyl)-4-hyd roxypyrrolidine-1-carboxylate (2) via a base-generated alkoxide. The mechanism of the migration is intramolecular, involving an unusual nine-membered cyclic transition state.

Full text of DOI:10.1016/j.tetlet.2010.03.009

Tetrahedron Letters 51 (2010) 2536–2538
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Tetrahedron Letters
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An alkoxide anion-triggered tert-butyloxycarbonyl group migration.
Mechanism and application
*
Fengtian Xue , Richard B. Silverman
Department of Chemistry, Department of Biochemistry, Molecular Biology, and Cell Biology, Center for Molecular Innovation and Drug Discovery,
Chemistry of Life Processes Institute, Northwestern University, 2145 Sheridan Road, Evanston, IL 60208-3113, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
We report a fast N?O tert-butyloxycarbonyl (Boc) migration of the imide (3R,4R)-tert-butyl 3-((6-(bis-
(tert-butoxycarbonyl)amino)-4-methylpyridin-2-yl)methyl)-4-hydroxypyrrolidine-1-carboxylate (2) via
a base-generated alkoxide. The mechanism of the migration is intramolecular, involving an unusual
nine-membered cyclic transition state.
Received 12 February 2010
Revised 26 February 2010
Accepted 1 March 2010
Available online 4 March 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
N to O migration
Boc group migration
Intramolecular migration
Cross-over experiment
In the course of research on the development of chiral pyrroli-
dine-based inhibitors for neuronal nitric oxide synthase (nNOS),
we evaluated various methods for the synthesis of compounds 1a
and 1b, the key intermediates to prepare drug candidates for dif-
ferent kinds of neurodegenerative diseases.1–3 Given the poor effi-
ciency of benzyl deprotection during the reported synthetic route
to 1a,2 we attempted to use bis-Boc protection of the amino group
on the pyridine ring (1b); these groups could be removed in one
step during the late stage deprotection of the synthesis in excellent
yields, providing a much more practical preparation of the final
products on a multi-gram scale.4
of this product did not match with those of the anticipated product
(1b). The isolated product has only an (M+H+) peak at 448, which is
100 less than the calculated molecular weight of 1b (M + H+ = 548),
implying a possible loss of one Boc group from the desired product.
This was further confirmed by the fact that there were two distinc-
tive singlets at 1.46 and 1.52 ppm (each integrating to nine pro-
tons) in the 1H NMR spectrum (in CDCl3) of the product. The
instability of the Boc-protecting group under strong basic condi-
tions has been documented.5,6 Interestingly, however, one broad
singlet in the 1H NMR spectrum was found from 2.30 to
2.40 ppm, indicating the presence of a hydroxyl group in the prod-
uct. Further NOSEY NMR data showed that the allyl group was con-
nected through the nitrogen atom of the amino functionality to the
pyridine ring.7 On the basis of these results, we assigned the prod-
uct as (3R,4R)-tert-butyl 3-((6-(allyl(tert-butoxycarbonyl)amino)-
4-methylpyridin-2-yl)methyl)-4-hydroxypyrrolidine-1-carboxyl-
ate (3).8 It was also noted that (1) compound 2 showed significant
stability in aqueous NaOH even at accelerated temperature9 and
(2) no O-allylation product was detected in the reaction process.
To elucidate the origin of N-allyl alcohol 3, the reaction was re-
peated and monitored closely by thin layer chromatography (TLC)
and LC/MS analysis. Time course studies clearly showed the disap-
pearance of the starting material (2) and the buildup of a new com-
pound with significantly less polarity when 2 was treated with
NaH in DMF. After the addition of H2O, the product (3), with similar
polarity to that of 2, was formed quickly (Scheme 1). Accordingly,
we speculated that the basic environment generated during the
quenching step catalyzed a hydrolysis reaction of the initial prod-
uct, leading to the formation of alcohol 3. To test this hypothesis,
Boc
N
Boc
N
R
N
O
1a R = Bn
1b R = Boc
To generate 1b, allylation of alcohol 2 was attempted by treat-
ing a solution of 2 in DMF with NaH (2 equiv) at room temperature,
followed by the addition of allyl bromide (2 equiv). The reaction
was quenched with H2O to form the product with 93% isolated
yield (Scheme 1). To our surprise, mass spectrum and 1H NMR data
* Corresponding author. Tel.: +1 847 491 5653; fax: +1 847 491 7713.
E-mail address: Agman@chem.northwestern.edu (R.B. Silverman).
Present address: Department of Chemistry, University of Louisiana at Lafayette,
PO Box 44370, Lafayette, LA 70504, USA.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.03.009

F. Xue, R. B. Silverman / Tetrahedron Letters 51 (2010) 2536–2538
2537
Boc
N
1) NaH
Boc
2) allyl bromide
3) H2O
N
Boc
N
N
O
1b
Boc
N
1) NaH
Boc
2) allyl bromide
3) H2O
Boc
N
N
N
OH
Boc
2
Boc
N
OH
3
Scheme 1. Formation of 3 from 2.
saturated aqueous NH4Cl before the addition of allyl bromide. As
seen in Scheme 4, compound 7 was isolated in quantitative yields
and characterized.16
Boc
N
1) NaH
2) sat. NH4Cl
O
Boc
To further investigate the reaction mechanism, we carried out a
cross-over experiment using a mixture of compounds 2 and 8 as
starting material. The mixture was treated with NaH, and after
5 min the reaction was quenched with saturated aqueous NH4Cl.
The reaction did not give any cross-over product (i.e., O-Boc-8) as
shown in Scheme 5: compound 7 was isolated in almost quantita-
tive yield, and compound 8 was fully recovered from the reaction
mixture. These results clearly indicate that the Boc migration reac-
tion takes place by an intramolecular pathway.
The unusual Boc-protecting group migration also provides a
facile approach to selectively add an allyl or a benzyl group onto
the amide N atom without hydroxyl group protection. The previous
method for this reaction suffered from competition of O-allylation
or O-benzylation reactions, leading to unsatisfactory yields of
products unless the hydroxyl group was protected (Scheme 6).2
Using di-Boc-protected 2 as the starting material, however, the
2
N
N
O
O
4
Scheme 2. Formation of 4 from 2.
the same reaction was repeated and quenched with saturated
aqueous NH4Cl to avoid the potential base-catalyzed hydrolysis
step. As a result, compound 4 was isolated in a 96% yield (Scheme
2).10 This result implies that a carbonate derivative was an inter-
mediate involved in the reaction course, which explains why there
was no O-allylation product formed from the reaction.
On the basis of this collected evidence, we propose that depro-
tonation of 2 by treatment with NaH forms 5 at the beginning of
the reaction (Scheme 3). Alkoxide 5 initiates the migration of one
of the two Boc groups on the aminopyridine through a nine-mem-
bered ring transition state to generate amide anion (6), which re-
acts with allyl bromide to generate 4. Several examples of anion-
triggered migration reactions have been described in the litera-
ture.11–15 The carbonate linkage of 4 is unstable to the strong basic
environment (e.g., aqueous NaOH, generated during the quenching
step) and is hydrolyzed quickly to give alcohol 3 as the only prod-
uct. To prove the presence of 6, the reaction was quenched with
Boc
N
1) NaH
2) sat. NH4Cl
O
2
BocHN
N
O
O
7
Scheme 4. Formation of 7 from 2.
Boc
N
Boc
N
O
NaH
Boc
Boc
2
N
N
O
O
N
N
O
5
6
O
O
Br
Boc
N
Boc
N
O
NaOH
Boc
Boc
N
N
OH
N
N
O
O
3
4
Scheme 3. Proposed mechanism for the formation of 3.

2538
F. Xue, R. B. Silverman / Tetrahedron Letters 51 (2010) 2536–2538
Boc
N
Boc
N
O
Boc
Boc
Boc
N
Boc
N
N
OH
OH
N
H
N
O
O
1) NaH
2) sat. NH4Cl
2
8
7 (95% from 2)
Boc
N
Boc
N
Boc
N
Bn
N
Bn
N
OH
8 (98% recovered)
Scheme 5. Cross-over experiment for Boc migration.
Boc
N
Boc
N
Boc
N
1) NaH
2) RBr
+
Boc
Boc
N
R
N
OH
N
R
N
OR
BocHN
N
OH
Scheme 6. Alkylation of the aminopyridine without hydroxyl protection.
9. Compound 2 was allowed to stir in a mixture of 1 N NaOH and MeOH (1:1) at
room temperature. After 30 min, only 15% of the hydrolyzed product (3R,4R)-
tert-butyl 3-((6-(tert-butoxycarbonylamino)-4-methylpyridin-2-yl)methyl)-4-
hydroxypyrrolidine-1-carboxylate was generated: 1H NMR (500 MHz, CDCl3) d
1.45–1.46 (m, 9H), 1.52 (s, 9H), 2.33 (s, 3H), 2.33–2.35 (br s, 1H), 2.70–2.80 (dt,
J = 6.0, 9.5 Hz, 1H), 2.80–2.85 (m, 1H), 3.15–3.20 (dt, J = 5.5, 10.5 Hz, 1H), 3.40–
3.55 (m, 2H), 3.58–3.62 (dd, J = 8.5, 10.0 Hz, 0.5H), 3.63–3.67 (dd, J = 8.5,
10.0 Hz, 0.5H), 4.09 (s, 1H), 4.75 (br s, 1H), 6.68–6.69 (d, J = 7.0 Hz, 1H), 7.19 (s,
1H), 7.68 (s, 1H); 13C NMR (125 MHz, CDCl3) d 21.1, 21.4, 28.2, 28.52, 28.54,
35.16, 35.24, 44.5, 45.2, 49.0, 49.5, 53.2, 53.6, 60.4, 70.3, 71.3, 79.2, 81.2, 110.6,
119.1, 119.2, 151.0, 151.1, 151.2, 152.2, 154.4, 157.4, 157.5; LC-TOF (M+H+)
calcd for C21H34N3O5 408.2498, found 408.2499.
reaction (e.g., allylation or benzylation) produces the desired com-
pound as the only product in excellent yields without interference
of side reactions at the hydroxyl group.
In summary, we demonstrated a novel alkoxide anion-triggered
N?O Boc migration involving an unusually large nine-membered
ring transition state. The Boc migration process provides a new
high yield method to perform selective amide allylation/benzyla-
tion over hydroxyl allylation/benzylation reactions.
Acknowledgment
10. Synthesis and characterization of (3R,4R)-tert-butyl 3-(allyloxy)-4-((6-
(bis(tert-butoxycarbonyl)amino)-4-methylpyridin-2-yl)methyl)pyrrolidine-1-
carboxylate (4). To a solution of 2 (505 mg, 1.0 mmol) in DMF (15 mL) was
added NaH (60% in mineral oil, 80 mg, 2.0 mmol) at room temperature. After
The authors are grateful for financial support from the National
Institutes of Health (GM049725).
5 min, allyl bromide (240 lL, 2.0 mmol) was added dropwise. The reaction
mixture was allowed to stir at room temperature for 30 min, then the reaction
was quenched with ice cold saturated NH4Cl (5.0 mL). The solvent was
removed in vacuo, and the resulting residue was purified by flash column
chromatography (silica gel, EtOAc/hexanes, 1:4) to yield 4 as a colorless oil
(525 mg, 96%): 1H NMR (500 MHz, CDCl3) d 1.42 (s, 9H), 1.47–1.49 (m, 18H),
2.25–2.27 (m, 3H), 2.70–2.85 (m, 2H), 2.89–2.93 (dd, J = 5.5, 13.0 Hz, 1H), 3.14–
3.21 (dd, J = 11.0, 21.5 Hz, 1H), 3.46–3.59 (m, 3H), 4.40–4.60 (m, 2H), 5.03–5.12
(m, 3H), 5.86–5.92 (ddd, J = 5.5, 12.0, 17.5 Hz, 1H), 6.64 (s, 1H), 7.32 (s, 0.5H),
7.36 (s, 0.5H); 13C NMR (125 MHz, CDCl3) d 21.11, 21.13, 27.8, 28.3, 28.47,
28.50, 34.7, 41.8, 42.3, 48.8, 49.06, 49.10, 49.2, 52.4, 52.8, 76.7, 76.8, 79.4, 80.9,
81.0, 82.4, 82.5, 115.8, 117.3, 117.4, 119.8, 134.91, 134.93, 148.5, 148.6, 153.1,
153.2, 153.9, 154.0, 154.1, 154.2, 154.4, 156.8; LC-TOF (M+H+) calcd for
C29H46N3O7 548.3336, found 548.3339.
References and notes
1. For a comprehensive review of the chemistry and biology related to the present
work, see: Silverman, R. B. Acc. Chem. Res. 2009, 42, 439.
2. Lawton, G. R.; Ranaivo, H. R.; Wing, L. K.; Ji, H.; Xue, F.; Martesek, P.; Roman, L.
J.; Watterson, D. M.; Silverman, R. B. Bioorg. Med. Chem. 2009, 17, 2371.
3. Xue, F.; Fang, J.; Lewis, W. W.; Martasek, P.; Roman, L. J.; Silverman, R. B. Bioorg.
Med. Chem. Lett. 2010, 20, 554.
4. A synthetic route using 2b as key intermediate for the preparation of multi-
gram scale drug candidates is complete.
5. Foillard, S.; Rasmussen, M. O.; Razkin, J.; Boturyn, D.; Dumy, P. J. Org. Chem.
2008, 73, 983.
11. Liu, Y.; Ding, Q.; Wu, X. J. Org. Chem. 2008, 73, 6025.
12. Gérard, S.; Marchand-Brynaert, J. Tetrahedron Lett. 2003, 44, 6339.
13. Hara, O.; Ito, M.; Hamada, Y. Tetrahedron Lett. 1998, 39, 5537.
6. Tom, N. J.; Simon, W. M.; Frost, H. N.; Ewing, M. Tetrahedron Lett. 2004, 45, 905.
7. Xue, F.; Silverman, R. B. unpublished result.
8. Synthesis and characterization of (3R,4R)-tert-butyl 3-(allyloxy)-4-((6-
(bis(tert-butoxycarbonyl)amino)-4-methylpyridin-2-yl)methyl)pyrrolidine-1-
carboxylate (3). To a solution of 2 (1.15 g, 2.0 mmol) in DMF (15 mL) was added
NaH (60% in mineral oil, 160 mg, 4.0 mmol) at room temperature. After five
14. Valentekovich, R. J.; Schreiber, S. L. J. Am. Chem. Soc. 1995, 117, 9069.
15. Bunch, L.; Norrby, P.-O.; Frydenvang, K.; Krogsgaard-Larsen, P.; Madsen, U. Org.
Lett. 2001, 3, 433.
16. Synthesis and characterization of (3R,4R)-tert-butyl 3-((6-(tert-butoxycarbonyl-
amino)-4-methylpyridin-2-yl)methyl)-4-(tert-butoxycarbonyloxy)pyrrolidine-
1-carboxylate (7). To a solution of 2 (250 mg, 0.5 mmol) in DMF (10 mL) was
added NaH (60% in mineral oil, 40 mg, 1.0 mmol) at room temperature. After
5 min, the reaction was quenched with saturated NH4Cl (5.0 mL). The solvent
was removed in vacuo, and the resulting residue was purified by flash column
chromatography (silica gel, EtOAc/hexanes, 1:4) to yield 4 as a colorless oil
(505 mg, 99%): 1H NMR (500 MHz, CDCl3) d 1.43–1.44 (m, 9H), 1.48–1.50 (m,
18H), 2.27–2.30 (m, 3H), 2.60–2.75 (m, 2H), 2.85–2.92 (m, 1H), 3.15–3.22 (dt,
J = 4.0, 11.0 Hz, 1H), 3.45–3.65 (m, 3H), 5.10 (br s, 1H), 6.60 (s, 1H), 7.13–7.17 (d,
J = 15.5 Hz, 1H), 7.58–7.60 (d, J = 9.0 Hz, 1H); 13C NMR (125 MHz, CDCl3) d 21.28,
21.30, 24.7, 27.79, 27.82, 28.3, 28.47, 28.50, 34.4, 34.5, 36.6, 42.0, 42.5, 48.9, 49.2,
52.5, 52.8, 76.2, 79.4, 79.5, 80.75, 80.80, 82.5, 110.18, 110.23, 115.8, 118.9, 150.0,
151.4, 151.5, 152.37, 152.41, 153.2, 153.3, 154.2, 154.4, 157.2, 157.3; LC-TOF
(M+H+) calcd for C26H42N3O5 508.3023, found 508.3037.
min, allyl bromide (480 lL, 4.0 mmol) was added. The reaction mixture was
allowed to stir at room temperature for 30 min, then the reaction was
quenched with H2O (5.0 mL). The solvents were removed by rotary evaporation
at 50 °C, and the resulting oil was purified by flash column chromatography
(silica gel, EtOAc/hexanes, 1:1) to yield 3 as a colorless oil (1.05 g, 93%): 1H
NMR (500 MHz, CDCl3) d 1.44–1.45 (m, 9H), 1.50 (m, 9H), 2.33 (s, 3H), 2.33–
2.38 (br s, 1H), 2.75–2.85 (dt, J = 5.0, 13.5 Hz, 1H), 2.85–2.93 (m, 1H), 3.16–3.22
(dt, J = 5.0, 10.5 Hz, 1H), 3.40–3.55 (m, 2H), 3.55–3.59 (t, J = 9.0 Hz, 0.5H), 3.62–
3.66 (t, J = 10.0 Hz, 1H), 4.05 (s, 1H), 4.20 (s, 0.5H), 4.38 (s, 0.5H), 4.43 (s, 2H),
5.07–5.12 (m, 2H), 5.85–6.00 (ddd, J = 5.0, 10.0, 15.5 Hz, 1H), 6.70–6.80 (m, 1H),
7.34 (s, 1H); 13C NMR (125 MHz, CDCl3) d 21.1, 21.2, 28.2, 28.51, 28.54, 35.3,
35.4, 44.7, 45.3, 49.1, 49.48, 49.52, 53.3, 53.6, 60.4, 70.2, 71.0, 79.1, 81.4, 115.7,
118.2, 120.2, 120.3, 134.35, 134.37, 149.5, 149.6, 154.0, 154.1, 154.4, 157.4,
157.5; LC-TOF (M+H+) calcd for C24H38N3O5 448.2811, found 448.2801.